Guide to MALARIA PHARMACOLOGY: introducing a new resource

gtommv_bannerWe are pleased to make public the first beta-release (v1.0) of the Guide to MALARIA PHARMACOLOGY (GtoMPdb), a new extension to the existing Guide to PHARMACOLOGY (GtoPdb). The GtoMPdb is being developed as a joint initiative between Medicines for Malaria Venture (MMV) and the International Union of Basic and Clinical Pharmacology (IUPHAR), with the aim of adding curated antimalarial data to GtoPdb and providing a purpose-built portal that is optimized for the malaria research community.

We have implemented a number of changes to the existing database structure and web interface that were necessary for the capture and presentation of antimalarial data. Many antimalarial compounds have a poorly understood mechanism of action and an unknown molecular target and we have extended the interactions table and updated the web interface to accommodate this. A new “whole organism” assay type has been introduced to capture data from the whole cell assays used routinely in antimalarial drug discovery. Both changes are illustrated below.

Figure 1: The interactions table on an antimalarial ligand summary page

Screen Shot 2019-02-25 at 15.02.56.png

In addition, we have put in place the ability to tag both targets and ligands of relevance to malaria and provide curatorial comments. These comments surface on the website (see Figure 2 below) and are incorporated into the site search.

Figure 2: Malaria comments tab on an antimalarial ligand summary page

Screen Shot 2019-02-25 at 11.42.59.png

A new GtoMPdb portal ( is being developed to provide tailored routes into browsing the antimalarial data in addition to the existing ligand and target browse/search functionality available on the parent GtoPdb site. For beta-release v1.0 we have implemented customised views of the data that include parasite lifecycle and target species activity, with access from either the menu-bar or panels on the homepage (see figure 3 below).

Figure 3: The GtoMPdb portal homepage

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The GtoMPdb uses a set of top-level Plasmodium lifecycle stages (collective categories for one or more developmental forms of the parasite) against which interactions in the database can be annotated and which form the basis of organising, navigating and searching for parasitic lifecycle activity. We have developed a new Parasite Lifecycle homepage that provides a short introduction and links to additional pages for each of the top-level lifecycle stages. These in turn contain a more detailed description and a table of interactions for that lifecycle stage (illustrated in Figure 4).

Figure 4: Plasmodium liver stage page, an example of the new Parasite Lifecycle Stage pages

Screen Shot 2019-02-25 at 11.17.10.png

The Target Species homepage provides a short description for Plasmodium species that are of clinical or research importance. It also includes a resource section and links to individual pages for species that have annotated interactions in the database. The figure below illustrates an example of an individual species page. The interactions table displays affinity data for the species but also provides additional details, when available, for the strain used.

Figure 5: Plasmodium falciparum page, an example of the new Target Species pages

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Development of the beta-release will continue with regular updates planned over the next few months as the quantity of data captured increases and improvements in the site layout and function are made.

If you have any feedback or queries about the resource please contact

This project is supported by a grant awarded to Professor Jamie Davies at the University of Edinburgh by Medicines for Malaria Venture (MMV).

Posted in Guide to Malaria Pharmacology, Technical

Hot Topics: Exciting Times for Ion Channel Pharmacology

Whilst life is always exciting as an ion channel pharmacologist, the last few months have been particularly so, with a large number of publications showing structures of ion channels with regulatory molecules bound to them. In just the last month, the journal, Science, has published several such papers. Three of these concern voltage-gated sodium channels (NaV1.2, NaV1.7) and the binding of potent and selective toxins from animals [1-3]. Another reveals the structure of the primary human cooling and menthol sensor channel TRPM8 bound to synthetic cooling and menthol-like compounds [4].

In the most recent paper [5], Schewe and colleagues extend their outstanding work on selectivity-filter gating of K2P potassium (K) channels (Schewe et al. (2016). Cell. PMID: 26919430), to identify a binding site for negatively charged activators of these channels (styled the “NCA binding site”). Activators which bind to this site open a number of different K2P channels (e.g. K2P2.1 (TREK-1) and K2P10.1 (TREK-2)) and several other potassium channels such as hERG channels (KV11.1) and BKCa channels (KCa1.1), all of which are gated at their selectivity filter. This is exciting, because it is notoriously difficult to design, or even identify, activator compounds for ion channels. This work together with the identification of a separate “cryptic binding site” for K2P channel activators (PMID: 28693035) opens possibilities for rationale design of activator compounds targeting these binding sites, which would provide potential novel therapeutic approaches for the treatment of several conditions including chronic pain, arrhythmias, epilepsy and migraine (PMID: 30573346).

One potential problem, identified by Schewe et al, is the promiscuity of the NCA binding site across several K channel families. However, there are enough structural differences in the region around the NCA-binding site between the channel types to overcome this. Provocatively, Schewe et al even suggest that the simultaneous activation of several different K channel types at once may even be advantageous in certain acute conditions such as ischemic stroke and status epilepticus.

Comments by Alistair Mathie (@AlistairMathie) and Emma L. Veale (@Ve11Emma), The Medway School of Pharmacy

(1) Clairfeuille T et al. (2019). Structural basis of α-scorpion toxin action on Nav channels. Science, pii: eaav8573. doi: 10.1126/science.aav8573. [PMIDs:30733386].

(2) Shen H et al. (2019). Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins. Science, pii: eaaw2493. doi: 10.1126/science.aaw2493. [Epub ahead of print]. [PMIDs:30765606].

(3) Pan X et al. (2019). Molecular basis for pore blockade of human NaNa+ channel Nav1.2 by the μ-conotoxin KIIIA. Science, pii: eaaw2999. doi: 10.1126/science.aaw2999. [Epub ahead of print]. [PMIDs:30765605].

(4) Yin Y et al. (2019). Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel. Science, pii: eaav9334. doi: 10.1126/science.aav9334. [Epub ahead of print]. [PMIDs:30733385].

(5) Schewe M et al. (2019). A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels. Science, 363(6429):875-880. doi: 10.1126/science.aav0569.. [PMIDs:30792303].


Posted in Hot Topics

Hot Topics: Ligand biological activity predicted by cleaning positive and negative chemical correlations

New machine learning algorithm for drug discovery that is twice as efficient as the industry standard and identified potential ligands for the M1 receptor, a potential target for the treatment of Alzheimer’s disease.

A paper from Lee et al. [1] (University of Cambridge) in collaboration with Pfizer, describes the development of an algorithm to use machine learning to separate pharmacologically relevant chemical patterns from irrelevant ones. The algorithm compared active versus inactive molecules at the muscarinic acetylcholine receptor, M1 and uses machine learning to identify components of the compounds are important for binding and which arose by chance. Lee et al. built a model using historic data using ~5,000 compounds that were screened for agonist activity, of which 222 were active. Six million molecules from the e−Molecules database were computationally screened. From these ~100 molecules were purchased and screened in CHO cells expressing the M1 receptor with four compounds identified as agonists (EC50 range 80-300nM).

Comments by Anthony Davenport, IUPHAR/BPS Guide to PHARMACOLOGY, University of Cambridge

(1) Lee AA et al. (2019). Ligand biological activity predicted by cleaning positive and negative chemical correlations. PNAS, [Epub ahead of print]. [PNAS: Article]

Posted in Hot Topics

Hot Topics: An online resource for GPCR structure determination and analysis

G protein-coupled receptors (GPCRs) transduce physiological and sensory stimuli into appropriate cellular responses and mediate the actions of one-third of drugs. Structures of GPCRs are therefore extremely valuable for understanding basic receptor function and rational drug design. Today, 310 structures of 59 distinct receptors ( have revealed the general bases of receptor activation, signalling, drug action and allosteric modulation. However, there are still no structures for the vast majority – 85% – of the 398 non-olfactory GPCRs and for 52% structure models can only be based on low-homology templates.

To accelerate the determination of GPCR structures and to help assess the quality of the available templates based on the modifications and methods, a recent article in Nature Methods presents “An Online Resource for GPCR Structure Determination and Analysis” [1]. This surveyes the construct engineering and experimental methods and reagens used to produce all available GPCR crystal and cryo-EM structures. Furthermore, it describes and interactive resource integrated in GPCRdb ( to assist users in designing new constructs and browsing appropriate experimental conditions for structure studies.

Comments by David E. Gloriam, University of Copenhagen (@David_Gloriam)

(1) Munk C et al. (2019). An online resource for GPCR structure determination and analysis. J Med Chem, doi:10.1038/s41592-018-0302-x. [PMID:30664776]


Posted in Hot Topics

Database Release 2019.1

Our first database release of 2019 (2019.1) is now available. This update contains the following new features and content changes:

Content Updates

GtoPdb contains over 9,400 ligands, with around 7,200 have quantitative interaction data to biological targets. Just over 1,400 of the ligands are approved drugs. The database contains over 1,700 human targets, with near 1,500 of these having quantitative interaction data. Full stats can be found on the About Page.

Targets curated in this release:




Official Launch, October 2018

At the beginning of October 2018 we held a meeting in Edinburgh focussed on the launch of the IUPHAR Guide to IMMUNOPHARMACOLOGY. Invited speakers contributed to productive discussions on the varying challenges and opportunities in immunopharmacology research. The meeting page has links to the slidesets from the meeting (where permission was granted) and to the meeting report which summarises the presentations, discussions and outcomes.


We have begun to incorporate direct links from our ligand pages to the Immunopaedia resource. Immunopaedia promotes education, knowledge and research in immunology globally; it is an immediate source of immunology information for healthcare professionals, students and researchers. Their clinical case studies utilise doctors’ real-world experiences to demonstrate diagnostic methods and treatments as well as explain immunological pathways of diseases. In close collaboration with colleagues at Immunopaedia we have put in place links to relevant case studies from our ligand summary pages (e.g. rituximab).

Guide to Malaria PHARAMCOLOGY

The first public beta-release (v1.0) of the IUPHAR/MMV Guide to Malaria PHARMACOLOGY ( is available in this release! The new portal has been designed to provide tailored routes into browsing the antimalarial data.

At this stage, the data curated in GtoMPdb and viewed on the Antimalarial targets family and the Antimalarial ligands family. In total the are 15 P. falciparum (3D7) targets and 50 ligands tagged as antimalarial in the database. A detailed blog-post on the release will be posted soon.

As well as being able to browse via target or ligand, users can also navigate data via parasite lifecycle stage and via target species. Search tools extended to cover GtoMPdb data, up weighting results relevant to malaria pharmacology.

Other Updates

Drug Approvals

There has been a substantially increased our coverage of European Medicines Agency (EMA) drug approval data in 2019.1. There are 414 approved drugs with EMA marked as a source, up from 274 in 2018.1.   In addition, at about this time of  year  considerable interest is generated from reviews of the previous year’s FDA Drug Approvals (see

Reaching 59, 2018 was welcomed as a particularly prolific year.  However, for our own capture, we have various exclusion criteria such as antiinfectives (with some exceptions including the antimalarials mentioned above), already-approved mixture components, topicals, non-antibody biologicals, undefined extracts (e.g. fish oil) and inorganics. Thus our scorecard stands at 26 chemical entities that form PubChem Compound Identifiers. We also have database records and PubChem Substance submissions for 11 of the 12 newly-approved antibodies (excepting the anti-HIV one).  Note the exact PubChem CID and SID counts will be linked here in a week or so and reviewed in forthcoming a blog post.

New Target: Vanin 1

Novel targets, as defined by first documentation of disease-targeted chemical modulators  (or new probes to explore roles of under-studied proteins) are relatively infrequent.  However, this release sees the first entry of Vanin 1 where inhibition is being explored as a novel mechanism for the treatment of inflammatory diseases.  This Boehringer filing WO2018228934 on Vanin inhibition with SAR for 44 compounds was found via filtered browsing of recent WO patents in SureChEMBL looking for new immunopharmacology indications in particular.

Update to CDK library to v2.2

We have updated the Chemical Development Kit (CDK) library to version 2.2. This is used by the Guide to Pharmacology to calculate molecular properties of ligands curated in the database. As part of this update, we performed a re-calculation of all molecular properties in the database. As a consequence, you may notice some difference between the properties in 2018.4 and 2019.1.

Chemicalize Pro API (Marvin JS update)

A key feature of the IUPHAR Guide to Pharmacology website is the ability to perform searches by chemical structure ( The chemical structure search tool utilises Marvin JS by ChemAxon. In the 2019.1 release we have updated the API control to use Chemicalize Pro ( This update simplifies the integration of Marvin JS into our website.

Page navigation

We have updated our webpages to feature a drop-down navigation bar, which is revealed when users scroll-down on longer pages. Many pages on GtoPdb are quite long, particularly detailed targets pages (e.g. CB1 receptor) – the new drop-down menu keeps key menu items, and most importantly the site search, in focus at all time.

Detailed target pages

Minor adjustments to the top-section of these pages to layout GtoImmuPdb and GtoMPdb icons and toggle button.

Posted in Database updates, Guide to Immunopharmacology, Guide to Malaria Pharmacology

Hot Topics: New Cannabinoid Receptors Structures

Cannabinoid receptors respond to multiple endogenous fatty acid derivatives and are often divided into neuronal-associated CB1 receptors and immune cell-associated CB2 receptors. Both receptors are GPCR, coupled predominantly to Gi, and have cytoprotective properties. The predominant psychotropic agent in Cannabis, THC, acts as a partial agonist at both receptors. CB1 patho/physiological responses are often characterised as analgesic, rewarding, orexigenic, hypothermic and amnestic, while CB2 receptors are mostly associated with anti-inflammatory effects.

In many countries, synthetic cannabinoids have become a social issue, with a prevalence of use amongst the homeless and incarcerated, with even a number of deaths attributed to these agents. Although all the molecular mechanisms of action of these synthetic cannabinoids are yet to be defined, one feature they have in common is a high potency and high efficacy profile at CB1 receptors. Kumar and colleagues [1] report a CB1 receptor:Gi complex, where the receptor is bound to a synthetic cannabinoid, MDMB-FUBINACA. The authors report an agonist binding-evoked conformational switch involving residues in TM3 and TM6, which they suggest underlies the high affinity of this synthetic cannabinoid. Furthermore, they conduct in silico simulations to suggest a lateral path of entry for the synthetic cannabinoid between TM1 and TM7 rather than the ‘traditional’ extracellular point of ingress. This lateral diffusion model has been suggested for a number of lipid-binding GPCR.

There is a second cannabinoid receptor crystal structure in the same journal, which focusses on the CB2 receptor [2]. Based on the primary sequences of the two human receptors, there is limited structural identity between CB1 and CB2 (~40 %), although the overlap is much higher in the transmembrane domains, as might be expected, given they bind a number of structurally-diverse ligands with little discrimination (e.g. CP55940, WIN55212-2 and HU210). Li et al report the first crystal structure of the CB2 receptor. In this version, a novel high affinity antagonist/inverse agonist AM10257 was bound to the receptor for crystallisation. The resultant structure shows a number of similarities with the antagonist-bound structure of the CB1 receptor, although notably the extracellular portions of the two receptors diverged markedly. Slightly surprisingly, a close resemblance to the agonist-bound CB1 receptor was identified, which lead them to investigate CB1 receptor function of the novel CB2 antagonist, which turned out to be a low efficacy CB1 receptor agonist.

Comments by Steve Alexander (@mqzspa)

[1] Kumar KK et al. (2018). Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. Cell, pii: S0092-8674(18)31565-4. doi: 10.1016/j.cell.2018.11.040. [Epub ahead of print]. [PMID:30639101].

[2] Li X et al. (2018). Crystal Structure of the Human Cannabinoid Receptor CB2. Cell, pii: S0092-8674(18)31625-8. doi: 10.1016/j.cell.2018.12.011. [Epub ahead of print]. [PMID:30639103].

Posted in Hot Topics

GtoPdb at BPS Pharmacology 2018

The IUPHAR/BPS Guide to Pharmacology was represented at the recent BPS Pharmacology 2018 meeting (London, UK, 18-20 Dec 2018).

Tuesday 18th Dec

On Tuesday we had two significant presentations. Firstly, a late-breaking poster on the IUPHAR/MMV Guide to Malaria Pharmacology. This is an under-development extension to the database to curate in anti-malarial ligands and Plasmodium targets for approved drugs.

Poster: Introducing a new resource: the capture of drugs, leads and targets in the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY (Presented by Dr. Chris Southan & Dr. Simon D. Harding)

Secondly, Dr. Southan presented on the challenges and tribulations of curating peptides in the Guide to Pharmacology. His slides are available below.

Oral Presentation: Tribulations of curating published key bioactive peptides for the Guide to PHARMACOLOGY

Thursday 20th Dec

On the Thursday by three more presentations. Firstly, Dr. Harding presented a flash presentation and poster on new features and updates to the Guide to Pharmacology in 2018, which was awarded the daily flash poster prize.

Poster: The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: new features and updates

Also during the poster session Dr. Southan presented his second poster looking at how we can identify the most pharmacologically significant proteins.

Poster: Will the real pharmacologically significant proteins please stand up?


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Posted in Events, Guide to Immunopharmacology, Guide to Malaria Pharmacology

Hot Topics: GPR37/GPR37L1 and the putative pairing with prosaptide/PSAP

Comments by Dr. Nicola J. Smith, National Heart Foundation Future Leader Fellow & Group Leader, Molecular Pharmacology Laboratory, Victor Chang Cardiac Research Institute, Australia

As is often the case with orphan GPCRs, assigning the endogenous ligand has been controversial for the closely related peptide family orphans, GPR37 and GPR37L1. In 2013, Randy Hall and his team (PubMed: 23690594) first reported an association between both centrally-expressed orphan GPCRs and prosaposin (PSAP) and prosaptide (TX14A), the synthetic active epitope of PSAP. Since that time there has been much debate in the field about whether this pairing is correct, with some authors corroborating the findings (PubMed: 24371137; 30010619, 28795439) and others not (PubMed: 23396314; 27072655; 28688853). Note that Head Activator, found in Hydra, was earlier reported as a ligand (PubMed: 16443751) but was quickly discredited (PubMed:28688853; 23686350).

A recent paper by Sergey Kasparov’s laboratory in Bristol has added further fuel to the fire. In a series of well controlled experiments, Liu et al. (PubMed: 30260505) provided convincing evidence that prosaptide is cyto- and neuro-protective and promotes chemotaxis. They are also the first group to demonstrate an effect of prosaptide at a more physiologically plausible potency. At the same time, Bang et al. (PubMed: 30010619) published a ground-breaking paper linking GPR37 expression to macrophage function. Moreover, they proposed a second, more potent ligand for GPR37 (GPR37L1 was not studied): the pro-resolving mediator neuroprotectin D1 (NPD1). Using HEK293 cells expressing GPR37, NPD1 was a potent stimulator of Gαi/o-dependent calcium flux; findings that were corroborated in macrophages isolated from wild type, but not GPR37 knock-out, mice (PubMed: 30010619). Thus, it may be that the endogenous ligand for GPR37 (and perhaps GPR37L1?) is not a peptide after all, but a lipid.

These two studies, while exciting, do little to help us resolve the conundrum that is PSAP/prosaptide and GPR37/GPR37L1. At the very least, it seems likely that prosaptide, if not the highest affinity endogenous ligand at GPR37, is certainly capable of signalling through GPR37 to stimulate Gαi/o signal transduction (whether it is the most potent endogenous agonist will be shown in time as independent groups seek to validate the actions of NPD1).

But what of GPR37L1? This is harder to answer as a number of studies linking GPR37L1 to PSAP/prosaptide have been performed in double GPR37/GPR37L1 knock-out backgrounds or inappropriate tissue models. For example, in the original paper connecting prosaptide to the receptors, the authors claimed prosaptide acted through both GPR37 and GPR37L1 in primary astrocytes, despite the fact that their Western blots demonstrated marked GPR37 expression in comparison to GPR37L1 in the cells (PubMed: 23690594). More recently, they failed to recapitulate this initial pairing in a HEK293 model (PubMed: 28688853). The absence of GPR37L1 in primary astrocytes is consistent with the animal knock-out work of Marazziti et al. (PubMed: 24062445), who showed that GPR37L1 protein was barely detectable before post-natal day 15, which is after the window for isolating primary astrocyte cultures (confirmed by PubMed: 28795439). Coleman et al. (PubMed: 27072655) overcame this expression issue, with difficulty, by using cerebellar slice cultures in vitro to examine Gαs, but not prosaptide, signalling in wild type and knock-out tissue.

In the neuroprotection paper by Liu et al. (PubMed: 30260505) it is clear that prosaptide or PSAP are exhibiting an effect on the cells. By depleting astrocytes of PSAP and then reintroducing prosaptide exogenously, there is an obvious effect on cell migration, cytotoxicity and neuroprotection – phenotypes that are all lost when shRNA knocking down expression of both GPR37 and GPR37L1 are used. Frustratingly, though, the use of a double knock-down approach makes it impossible to ascribe a specific effect to GPR37L1. While GPR37 and GPR37L1 are very closely related by phylogeny and have highly similsar binding sites (PubMed: 27992882), this does not mean that prosaptide is a ligand at both receptors, nor that both receptors signal via the same G proteins (another area of controversy for GPR37L1, where contradictory studies including two by the same team show either Gαi/o or Gαs signaling: PubMed: 23690594, 30260505 vs 27072655, 28688853). Thus, the failure to use single receptor knock-out/knock-downs, or isolate cells with endogenous expression of GPR37L1, represent major limitations in these studies.

Other than the confounding effects of both GPR37 and GPR37L1 deletion in tested cells, what are other reasons that could explain the inconsistencies between studies? Kasparov and colleagues (PubMed: 30260505) attribute this to cellular background, stating that previous studies that failed to confirm prosaptide/GPR37L1 coupling (PubMed: 27072655, 28688853) used HEK293 cells that must be lacking in the necessary endogenous machinery for signal transduction (PubMed: 30260505). To support this claim, they turned to the PRESTO-Tango assay in HEK293 cells to demonstrate prosaptide stimulation could not lead to GPR37L1-dependent recruitment of beta-arrestin. The assay choice is surprising because previous beta-arrestin-based screens at GPR37L1 have failed to show that the receptor can indeed recruit arrestins (PubMed: 23396314, 25895059), and Liu et al. (PubMed: 30260505) did not provide evidence that recruitment was intact in a more physiologically relevant cellular background. Most puzzling though is that the original paper that identified prosaptide and PSAP as GPR37/37L1 ligands used HEK293 cells to make the original pairing (PubMed: 23690594). They also refute the physiological relevance of high constitutive Gαs signalling reported by Coleman et al., even though Coleman et al. demonstrated higher cAMP accumulation in cerebellar brain slices from wild type mice when compared to GPR37L1-/- (PubMed: 27072655).

Further muddying the waters, the physiological role of GPR37L1 itself remains enigmatic. For example, Min et al. (PubMed: 20100464) initially reported GPR37L1 null mice to have a staggering 62 mmHg increase in systolic blood pressure when compared to a cardiac-specific overexpressing model, with the presence of concomitant left ventricular hypertrophy. However, Coleman et al. (PubMed: 29625592) found a far more marginal cardiovascular phenotype, with a small increase in blood pressure evident in female mice only. Notably, male GPR37L1 knock-out mice appeared to be more susceptible to cardiovascular stressors, while females were cardioprotected (PubMed: 29625592). In terms of a developmental phenotype, Marazziti et al. (PubMed: 24062445) found that GPR37L1 null mice displayed precocious cerebellar development with enhanced performance in a rotarod test up to 1 year of age. More recently, though, Jolly et al. (PubMed: 28795439) failed to confirm a behavioural difference in their own GPR37L1 knock out mice. The links between GPR37L1 and neurological defects are also confounded by the fact that GPR37 also needs to be deleted in mice for a clear phenotype to be evident. For example, while a single point mutation in GPR37L1 (K349N) in a highly consanguineous family appeared to be causative of fatal progressive myoclonus epilepsy, the mouse phenotype was most pronounced in double GPR37/GPR37L1 knock-out animals (PubMed: 28688853). In vitro studies of the GPR37L1 K349N mutant found no difference between it and the wild type receptor in terms of receptor expression, processing, signalling or ubiquitination (PubMed: 28688853). In the absence of a transgenic K349N mutant mouse, or any confirmed synthetic agonists or antagonists, the authors then assessed seizure susceptibility in knock-out mice of either GPR37L1, GPR37 or both receptors. Interestingly, using the 6Hz-induced seizure model, the GPR37-/- mice appeared to have a more pronounced phenotype than the GPR37L1-/- mice, while double KO mice were extremely susceptible to seizures at all frequencies tested. GPR37 and double KO mice both displayed more spontaneous seizures, although curiously in the flurothyl-induced seizure model only GPR37L1-/- differed from wild type. Thus, conclusive links between GPR37L1 and a specific physiological or pathophysiological state remain to be provided and it seems in general that we are far from understanding the true biology and pharmacology of the receptor.


Posted in Hot Topics

Hot Topics: Somatic APP gene recombination in normal and Alzheimer’s disease neurons

A new facet of the human brain has been reported [1] involving a first example of somatic gene recombination in neurons, representing a normal neural mechanism whose disruption could underlie the most common (sporadic) forms of Alzheimer’s disease. Mosaic and somatic recombination of Amyloid Precursor Protein (APP) was identified in this well-known Alzheimer’s disease gene, where increased copies and mutations in rare families or Down syndrome are considered causal. Recombination generates thousands of previously unknown gene variants characterized as “genomic complementary DNAs” or “gencDNAs” that could show identical sequences to cDNAs copied from brain-specific spliced RNAs, as well as myriad truncated forms characterized by exonic deletions and “intraexonic junctions” to produce novel sequences that become “retro-inserted” into the genome of single neurons, with neurons showing from 0 to 13 copies. Recombination appeared to require gene transcription, reverse transcriptase activity and DNA strand breaks. Both forms and numbers of APP gencDNAs were altered and increased in sporadic Alzheimer’s disease. Recombination might normally provide a way to alter post-mitotic neuronal genomes to “record” preferred gene variants for later “playback” without a need for gene splicing, towards optimizing or fine-tuning gene expression, representing a form of memory. The involvement of reverse transcriptase activities implicate potential Alzheimer’s disease therapeutics using reverse transcriptase inhibitors, a possibility supported epidemiologically by relatively rare cases of Alzheimer’s disease in aged HIV patients. Recombination could generate new therapeutic targets. Other recombined genes and affected diseases are possible.

Comments by Jerold Chun, Sanford Burnham Prebys Medical Discovery Institute

(1) Lee MH et al. (2018). Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature, doi: 10.1038/s41586-018-0718-6. [Epub ahead of print]. [PMID:30464338].

Posted in Hot Topics

Hot Topics: Cellular thermal shift assays to measure ligand-to-target engagement

The cellular thermal shift assay (CETSA) was introduced in July of 2013 as a means to investigate drug target engagement inside live cells and tissues (1). The underlying principle of CETSA is simple – it relies on the thermostability of each investigated protein and how this is altered by ligand binding. Experimentally these changes are assessed by applying a transient heat-pulse to the samples. This results in rapid rearrangements of established equilibria such that proteins denature and aggregate unless stabilised by ligand (1,2). The simplicity of CETSA has allowed prompt adoption in the literature but the importance of rapid changes in ligand binding is still not well recognised.

To explore these considerations we systematically varied both the heat-pulse temperature and duration in CETSA using p38a as our model system (3). Studies spanning seven different heating times and over a 13°C temperature interval show apparent potency changes over four orders of magnitude. These studies demonstrate how quantitative comparisons with functional cellular data require an understanding of the temperature dependence of the interactions under study. Our publications also discuss critical technology developments that allow shorter heating times.  These can now be down in the 10s of seconds range to minimize ligand rearrangements and heat-induced changes to cell permeability.

Comments by Dr. Thomas Lundbäck,  Associate Director, Mechanistic Biology & Profiling, Discovery Sciences, AstraZeneca R&D, Gothenburg,  Sweden,

  1. Martinez Molina, D.; Jafari, R.; Ignatushchenko, M.; Seki, T.; Larsson, E. A.; Dan, C.; Sreekumar, L.; Cao, Y.; Nordlund, P., Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science 2013, 341 (6141), 84-7 (PMID 23828940).
  2.  Jafari, R.; Almqvist, H.; Axelsson, H.; Ignatushchenko, M.; Lundbäck, T.; Nordlund, P.; Martinez Molina, D., The cellular thermal shift assay for evaluating drug-target interactions in cells. Nat Protoc 2014, 9 (9), 2100-22 (PMID 25101824).
  3.  Seashore-Ludlow, B.; Axelsson, H.; Almqvist, H.; Dahlgren, B.; Jonsson, M.; Lundbäck, T., Quantitative Interpretation of Intracellular Drug Binding and Kinetics Using the Cellular Thermal Shift Assay. Biochemistry Nov 2018 (PMID 30418016).
Posted in Hot Topics

Immunopharmacology: challenges, opportunities and research tools. Edinburgh 1st-2nd October 2018.

At the beginning of October 2018 we held a meeting in Edinburgh focussed on the launch of the IUPHAR Guide to IMMUNOPHARMACOLOGY. Invited speakers contributed to productive discussions on the varying challenges and opportunities in immunopharmacology research.

Immunopharmacology: The New Frontier

There has been immense progress in immunopharmacology, but there are insufficient links between the immunological and pharmacological sciences. Thus, we have set up several initiatives.

  • IUPHAR set up an immunopharmacology section (Immuphar) chaired by Francesca Levi-Schaffer.

  • IUPHAR has signed an agreement with International Union of Immunological Sciences (IUIS, President Alberto Mantovani, who has also made major contributions to the field of check-point inhibitors) to ensure collaboration and cooperation.

  • IUPHAR, NC-IUPHAR (chair Steve Alexander), the University of Edinburgh (PI, Pr Jamie Davies) and the Edinburgh database group (IUPHAR/BPS Guide to Pharmacology; have been able to set up a new database on the drug targets in immunopharmacology, financed by a major grant from the Wellcome Trust. This is, which has been recently launched and is freely available to all. The BPS finance two staff in the Edinburgh group for which IUPHAR is immensely grateful.

  • To celebrate this launch, a focussed immunopharmacology meeting was organised, which included the Anthony Harmar memorial lecture. This report provides a a summary of the meeting presentations, discussions and outcomes.

The launch of GtoImmuPdb has also been reported in a Nature Review Immunology Web Watch article: Harding SD et al. (2018). A new guide to immunopharmacology. Nat Rev Immunol, 18(12):729. [PMID:30327546]

Please read our detail meeting report which summarises the presentations, discussions and outcomes. Download the Meeting Report (PDF)

Access slidesets from the presentations below (or on our website):

Meeting Presentations

Anthony Harmer Memorial Lecture: Decision-making in lung immunity Prof. Tracy Hussell Download slides: pptx | pdf
The Guide to IMMUNOPHARMACOLOGY Dr. Elena Faccenda, Dr. Chris Southan and Dr. Simon Harding Download slides: pptx | pdf
Macrophage plasticity in immunopathology and cancer: from bench to bedside Prof. Alberto Mantovani Download slides: pptx | pdf
Targeting Pattern Recognition Receptor signalling for therapeutic approaches Prof. Clare Bryant slides not available
Discovering the right target in inflammatory disease Prof. Iain McInnes slides not available
Is Atherosclerosis a Systemic or a Vascular Immune Disease? Prof. Pasquale Maffia slides not available
Inhibit Activation or Activate Inhibition of Mast Cells and Eosinophils: Which Weapon is Better to Fight Allergic Diseases? Prof. Francesca Levi-Schaffer Download slides: pptx | pdf
IUPHAR: natural products and immunology Prof. Michael Spedding Download slides: pptx | pdf
Human type I interferon up regulation – worth targeting? Prof. Yanick Crow Download slides: pptx | pdf
A review on kinase targets in immunological indications Dr. Dorian Fabbro Download slides: pdf
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Posted in Events, Guide to Immunopharmacology

The Anthony Harmar Memorial Lecture 2018: Prof. Tracy Hussell

Prof. Tracy Hussell

Lung Disease: think about disease in a different way

Hussell Tracey (Altered)Tracy Hussell is Director, Manchester Collaborative Centre for Inflammation Research (MCCIR) and Professor of Inflammatory Disease, University of Manchester, Oxford Road, Manchester, M13 9PT.

To be healthy is an active process so health must be continually maintained. Is disease a process that can’t sense it is healthy again? We all have different set points. Sterile inflammation can be created by a single missing factor. Generally, while the lung epithelium is intact, then the tissue is non-activated. Epithelial damage is a critical driver, which may permanently change macrophages and the basal state in the lung. Airways macrophages are critical – when washed out, tissues change very quickly.

CD200R transmits negative signal to macrophages and ligand is on epithelium cells. Then antigen relieves signal. Axl continually recognises gas 6 on apoptosis so don’t activate with apoptosis.

Resolution of inflammation gives a different macrophage population – twice as many as before inflammation, which may survey the environment, resolving from a severe inflammatory event, to a new state. There are therapeutic ways of going back, but chronic obstructive pulmonary disease (COPD) and asthma have a permanently active state. MiRNAs are changed in resolved inflammation, therefore let-7b is increased, modifying Toll response changes. Patient becomes less responsive to bacteria – patients are retuned to not die when challenged, but have also lost miRNAs. The basement membrane is normally very thin but becomes permanently changed (Burgstaller et al., 2017, Eur Respir J. 2017 doi: 10.1183/13993003. PMID: 28679607). The tissue is changed, so not just immune effects.

Hyaluranon is a major constituent of the inflamed lung. Is the lung inflamed or is it just because there are a lot of retained immune cells? The latter. Why does matrix persist? Hyaluronic acid synthase is increased (clearance unchanged, hyaluronase unchanged). Matrix turnover means that there are more activated immune cells. The impact of viral infections on lung matrix affects its mechanical stability and structural support. The composition of matrix also indirectly controls inflammation by influencing cell adhesion, migration, survival, proliferation and differentiation. Hyaluronan is a significant component of the lung extracellular matrix and production and degradation must be carefully balanced. Tracy discovered an imbalance in hyaluronan production following resolution of a severe lung influenza virus infection, driven by hyaluronan synthase 2 from epithelial cells, endothelial cells and fibroblasts. Furthermore hyaluronan, due to elevated TNF, sequesters CD44-expressing macrophages. Intranasal hyaluronidase reduces lung hyaluronan restoring function. Hyaluronidase is already used clinically. Digestion of HA restores lung function. Hyaluronidase (available for clinical trials) appears an interesting option. (Hussell T et al., Eur Respir Rev., 2018, doi: 10.1183/16000617.0032-2018. PMID: 29950305).

In cancer the matrix is abnormal, and the immune system is paralysed. In many instances the matrix is stiff. It may be possible to think differently about reactivating the immune system here.

In severe cell death, macrophages clear apoptotic cells, TAMs recognise external phosphatidyl serine. Reverse signalling to STAT1 turning off inflammation, so while apoptosis is going on the tissue is vulnerable to bacterial attack. Axl receptor only in lung so this represents a unique opportunity for targeted therapy. Changed matrix, lost apoptosis, but poorly cleared even if immunity suppressed.

Eight days after influenza, basal cells proliferate requiring Axl receptor to show that damage has happened. Basal cell show hyperplasia if apoptosis continues – most lung disease has this as a hallmark. Axl antagonists allows faster repair. Type 1 interferons (IFNs): Neuropeptide receptors alter away homeostasis Gfra2 part of GDNF family massively increased on lung TAMs. Needs to co-stimulate with ret which is induced by type 1 IFNs. The virus may act via TLR7/8, in epithelium. MMP2 is specifically increased to degrade collagen type IV to degrade basement membrane. Two chemokines bind CXCR2. CCL18 macrophages that drive resolution, no homologue in rodents.

Is COPD then associated with inflamed tissues or trapped inflammatory cells? Possibly like tumours. Will check-point inhibitors also release antigen presenting cells? New therapeutic options await validation.

Slide Downloads: PPTX | PDF


Anthony Harmar, Professor of Pharmacology in Edinburgh.

In addition to being a brilliant pharmacologist, Tony set up the IUPHAR Edinburgh database group which initiated IUPHAR-DB, which expanded into the IUPHAR/BPS Guide to Pharmacology database (


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Posted in Events

Hot Topics: Piezo channels and mechano-transduction in sensory neurons

Piezo channels (Piezo1 and Piezo2) are excitatory ion channels which respond directly to a variety of forms of mechanical stimuli. Two recent papers describe some of the critical roles of Piezo channels in sensory neuron transduction (1, 2). In the first, Murthy et al. (1) demonstrate that Piezo2 mediates both inflammatory and nerve-injury sensitized mechanical pain in mice. In the second, Zeng et al. (2), show that both Piezo1 and Piezo2 are responsible for the baro-receptor reflex that regulates blood pressure and cardiac function.

For researchers interested in studying the roles of Piezo channels in mechano-transduction, useful pharmacological tools, at least for Piezo1, in the form of allosteric activators (3) and an inhibitor (4), have already emerged. Named Yoda1, Jedi1, Jedi2 and Dooku1, they are. May the force………

Comments by Alistair Mathie (@AlistairMathie) and Emma L. Veale (@Ve11Emma), The Medway School of Pharmacy

(1) Murthy SE et al. (2018). The mechanosensitive ion channel Piezo2 mediates sensitivity to mechanical pain in mice. Sci Transl Med. doi: 10.1126/scitranslmed.aat9897. [PMID: 30305457].
(2) Zeng WZ et al. (2018). PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex. Science doi: 10.1126/science.aau6324. [PMID: 30361375].
(3) Wang Y et al. (2018). A lever-like transduction pathway for long-distance chemical- and mechano-gating of the mechanosensitive Piezo1 channel. Nat Commun. 9(1):1300. doi: 10.1038/s41467-018-03570-9. [PMID: 29610524].
(4) Evans EL et al. (2018). Yoda1 analogue (Dooku1) which antagonizes Yoda1-evoked activation of Piezo1 and aortic relaxation. Br J Pharmacol. 175(10):1744-1759. doi: 10.1111/bph.14188. [PMID: 29498036].

Posted in Hot Topics

Hot Topics: Role of RTP type D on reward association with cocaine administration

The receptor tyrosine phosphatase (RTP) family is a relatively small group of cell-surface proteins with a simple intracellular enzymatic function in the dephosphorylation of phosphotyrosine proteins. There is less known about the endogenous extracellular ligands which regulate RTP activities in physiological conditions, although some RTPs are activated by cell-surface proteins thought to be expressed on neighbouring cells.

This report [1] from the National Institute on Drug Abuse in the USA focusses on the role of RTP type D on reward associated with cocaine administration. They identify that RTP type D heterozygous knockout mice exhibit lower reward responses to cocaine, and that a novel small molecule that appears to target the enzymatic function of RTP type D is able to reduce cocaine-induced place preference and self-administration in wild type, but not heterozygous knockout mice.

Comments by Steve Alexander (@mqzspa)

(1) Uhl GR et al. (2018). β-Subunit of the voltage-gated Ca2+ channel Cav1.2 drives signaling to the nucleus via H-Ras. Proc Natl Acad Sci USA, pii: 201720446. doi: 10.1073/pnas.1720446115. [Epub ahead of print] [PMID: 30348770]

Posted in Hot Topics

Hot topic: (but in this case, stale beer) the long overdue primary pharmacological characterisation of BIA 10-2747

The unfortunate French clinical trial disaster in which the FAAH inhibitor BIA 10-2747 (ligand ID 9001)  left one participant dead and several others with serious neurological adverse events, occurred back in January 2016.  However, the primary publication that describes the properties of this lead compound from its Portuguese originators BIAL has only now appeared in September of 2018 (1).  It is more typical for pharmaceutical medicinal chemistry teams to report their initial in vitro optimisation of a clinical candidate well in advance of Phase 1 (i.e. we might have expected to see this paper circa 2017).  While much has been written about 10-2747 in the last two years, very little peer-reviewed data has appeared (see this slide set and blog post).  In this context, the only BIAL journal paper so far on this compound is a disappointment.  The SAR of the series is only reported as % inhibition determinations rather than the more standardised and usefully comparative IC50s (this means we would actually not curate interaction data from such a paper but we have added the reference to the ligand entry). In addition, they do not address experimentally the irreversibility topic over which there has been some confusion. We would also quibble with the use of  “potent” in the title since an independent report of the initial IC50 binding  (i.e. without pre-incubation for inactivation) was only 7.5 uM (2).

Comments by Chris Southan (@cdsouthan)

  1. Kiss et al  (2018). Discovery of a Potent, Long-Acting, and CNS-Active Inhibitor (BIA 10-2474) of Fatty Acid Amide Hydrolase.  ChemMedChem, [Epub ahead of print]. [PMID:30113139].
  2. van Esbroeck et al. (2017) Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474 Science, 356(6342):1084-1087 (PMID: 28596366)


Posted in Hot Topics

Hot Topics: Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor

In this multi-author, multi-centre publication [1] lead by Denise Wootten and Patrick Sexton from the Monash Institute of Pharmacological Sciences, there is reported a 3.3 Angstrom structure of one of the more unusual G protein-coupled receptors. The CGRP receptor is a target for the recently FDA-approved monoclonal antibody erenumab targetting migraine. The receptor is unusual because of its modulation by a trio of accessory proteins exemplified here by RAMP1, which influence both the pharmacological and signalling profiles of the GPCR. Recent structural approaches to studies of GPCR have moved into investigations where a G protein is included. The Liang paper has a Gs heterotrimer attached, and, in addition, has the natural ligand, CGRP bound to the receptor. The report on this six molecule complex thus allows a major advance into the interaction between a GPCR, its endogenous agonist, the requisite G protein AND a modulatory protein.

Comments by Steve Alexander (@mqzspa)

(1) Liang YL et al. (2018). Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor. Nature, doi: 10.1038/s41586-018-0535-y. [Epub ahead of print]. [PMID: 30175587]

Posted in Hot Topics

Hot Topics: β-Subunit of the voltage-gated Ca2+ channel Cav1.2 drives signaling to the nucleus via H-Ras

This paper [1] extends previous studies demonstrating a key role of voltage-gated L-type Ca2+ channels in the modulation of activity-dependent gene transcription. Earlier work in cultured neurons had already shown that L-type channel activity is required to activate gene expression through different signaling pathways, including the Ras/MAPK pathway [2-4]. This is confirmed in the present study (primarily in experiments with HEK-293 cells) but there are important differences in the way nuclear signaling gets activated. In contrast to previous models [2], it is shown that the Ras/MAPK pathway is turned on by a direct physical interaction of the L-type channel (only Cav1.2 was studied) with Ras through the channel’s beta-subunit. Moreover, this interaction requires binding of extracellular Ca2+ to the pore-forming alpha1-subunit but no Ca2+ influx through the channel. Also no binding of calmodulin to the channel is required. This strongly suggests a direct conformational coupling of Cav1.2 to Ras activation and adds to other evidence of conformational coupling of L-type Ca2+ channels [5-6]. However, further experiments are required to demonstrate that this mechanism also exists in neurons.

Comments by Jörg Striessnig, University of Innsbruck

(1) Servili E et al. (2018). β-Subunit of the voltage-gated Ca2+ channel Cav1.2 drives signaling to the nucleus via H-Ras. Proc Natl Acad Sci USA, 115(37):E8624-E8633. doi: 10.1073/pnas.1805380115. [PMID: 30150369]

(2) Dolmetsch RE et al. (2001). Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science, 294(5541):333-9. [PMID: 11598293]

(3) Wu GY et al. (2018). Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Cold Spring Harbor Perspect Biol, 98(5):2808-13. [PMID: 11226322]

(4) Hagenston AM & Bading H (2018). Calcium signaling in synapse-to-nucleus communication. Mol Pharmacol, 3(11):a004564. doi: 10.1101/cshperspect.a004564. [Epub ahead of print]. [PMID: 30021858]

(5) Krey JF et al. (2013). Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nat Neurosci 16:201-9. [PMID: 23313911]

(6) Li B et al. (2016). Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression. Science 351:863-7. [PMID: 26912895]

Posted in Hot Topics

Database release 2018.4

Our fourth database release of the year, 2018.4, is now available (n.b. the PubChem update statistics and link sets will be posted in a couple of weeks).   This update contains the following new features and content changes:

Content Updates



Ion Channels:


Catalytic Receptors:


Other Proteins:


Recently added immunology/inflammation targets with novel pharmacological modulators include:

  • Fc fragment of IgG receptor IIIa (FCGR3A)
  • RAS guanyl releasing protein 1 (RASGRP1)
  • transglutaminase 2 (TGM2)
  • sialic acid binding Ig like lectin 8 (SIGLEC8)
  • CD37
  • signal transducer and activator of transcription 3 (STAT3)
  • signal transducer and activator of transcription 6 (STAT6)

In response to publication of ‘Ion channelopathies of the immune system’ (Vaeth and Feske, 2018; PMID:29635109), we have updated the immune cell type and GtoImmuPdb curation for the ion channels and transporters that the article and the ‘Guide’ have in common.

Guide to Malaria PHARAMCOLOGY

The Antimalarial targets family and the Antimalarial ligands family have been updated, giving a total of 9 P. falciparum (3D7) targets and 41 ligands tagged as antimalarial in the database.

Peptide Curation

Over the summer a MSc student, Lin Yakai, worked on a project to investigate GtoPdb peptide ligand structures and develop ways of converting these into standardised specifications (SMILES, InChi, HELM etc.). Using SugarNSplice software (SnS) we have been able to convert some peptides to SMILES format and submit these to PubChem – creating new CIDs from our SID structures. At this stage, we have converted ~400 peptides and on this release have curated the SMILES of around 40 peptides back into GtoPdb.  One of these includes the venerable “Entothelin-1” (Ligand ID 989)  that now specifies not only peptide sequence but also points to the CID.  There is a preliminary slide set on this topic but we will publish a detailed blog post in due course.

Other Announcements

  • We have now broken the 10,000 barrier for ligand IDs on the development server. However, it will still be some time before our PubChem SIDs hit this number since there have been a number of internal deprecations of superseded entries.
  • Ligand 10083 represents a new precedent in being curated from ChemRxiv,  The Preprint Server for Chemistry (where we have two papers that were subsequently published by ACS Omega). This gives us the advantage of being able to pick up key bioactive chemistry from open manuscripts many months before the papers are accepted and indexed in PubMed (using a DOI to enter the reference in our system).  This case was a cell-penetrant KDM5B covalent inhibitor with therapeutic relevance to immunopharmacology and cancer. The authors are from the Structural Genomics Consortium (SGC)
  • Nearly three years after the clinical trial fatality in January 2016  the primary pharmacological characterization paper for BIA-10-2747 has finally appeared (see Hot Topic report)

New website features

Extension to web-services

With the continuing development of the GtoImmuPdb we are pleased to announce that target and ligands of immunological relevance, as well as the new immunopharmacology data types can now be retrieved via our web services.

For example, targets tagged in the database as relevant to immunopharmacology can be retrieved form the following URL:

The API has also been extended to return immuno processes and cell types for specific targets. Here is an example retrieving cell types associated with CD86 (target ID 2735):

We have also introduced disease data to the web services, so summarised data for any disease in GtoPdb can be retrieved, here using Psoriasis (disease ID 801) as an example:


We have extended the file formats to include both csv and tsv formats on our downloads page.


We have extended our about page to include a few extra statistics on ligand counts with clinical use summaries and interactions.

Posted in Database updates, Guide to Immunopharmacology, Guide to Malaria Pharmacology

July 2018 News, Updates and Hot Topics

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July 2018

News, Updates and Hot Topics

Database release 2018.3:

Our third database release of the year, 2018.3, is now available. This update contains the following new features and content changes:

  • Updates across several target classes.
  • The existing Antimalarial targets family has been updated with 5 new P. falciparum (3D7) targets:
    • PfATP4 (Plasmodium falciparum ATPase4)
    • PfDHFR-TS (Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase)
    • PfDXR (Plasmodium falciparum 1-deoxy-D-xylulose 5-phosphate reductoisomerase)
    • PfeEF2 (Plasmodium falciparum elongation factor 2)
    • PfPI4K (Plasmodium falciparum phosphatidylinositol 4-kinase)
  • A new Antimalarial ligands family has been created and contains 30 ligands all tagged as an antimalarial in the database. Of these 30, 20 are new ligands curated for this release.
  • GtoImmuPdb now public

The IUPHAR Guide to IMMUNOPHARMACOLOGY is now at its first public release and is no longer considered a beta version. We will continue to develop the portal and specific immuno interfaces as well as continuing curation towards its official launch in October 2018 (see blog post here

Recent Papers from the Team

We are pleased to point to three.  Two were close in succession, both initially as pre-prints in ChemRxiv and later accepted in ACS Omega.  Both are Open Acess and will be full-text indexed in  PubMed Central and European PubMed Central in due course.

“SynPharm: A Guide to PHARMACOLOGY Database Tool for Designing Drug Control into Engineered Proteins” Ireland

“Challenges of Connecting Chemistry to Pharmacology: Perspectives from Curating the IUPHAR/BPS Guide to PHARMACOLOGY”  Southan et. al. DOI/10.1021/acsomega.8b00884.

The third has been on the Current Protocols in Bioinformatics website for some months but was only just recently indexed in PubMed as “Accessing Expert-Curated Pharmacological Data in the IUPHAR/BPS Guide to PHARMACOLOGY”  Sharman et. al. PMID 30040201.

Hot Topics

The Guide to PHARMACOLOGY hot topics are new and significant pharmacology, drug discovery and key human genomics papers. These are often communicated to us through our expert subcommittee members. All hot topic papers are listed on the hot topics page on the website ( For a selection, we commission concise commentaries from our expert contacts and these are posted onto our blog (

Here we summarise the latest hot topic commentaries:

New pharmacological tools reiterate lack of direct connection between Angiotensin 1–7 and the MAS1 GPCR

Comments by Sadashiva S. Karnik ( and Kalyan Tirupula

A new type of deorphanization conundrum confronted in pairing the GPCR, MAS1 with the hormonal peptide angiotensin 1–7 (Ang1-7) was emphasised in recent IUPHAR reviews… Read more.

Structural details for coupling of the agonist-occupied µ opioid receptor (amongst others) to the Gi protein

Comments by Eamonn Kelly ( and Katy Sutcliffe

Every few years in the field of receptor pharmacology, a technological advance occurs that drives the field forward in terms of insight and understanding. Over the past couple of years, the cryo-EM technique (the development of which won the 2017 Nobel Prize in Chemistry for Dubochet, Frank, and Henderson) for resolving protein structures… Read more.

Systems Medicine, Disease Maps and the future of Systems Biology

Comments by Steven Watterson (@systemsbiology), University of Ulster

What will Systems Biology look like in the future? Up to now, it has focussed on the development of standards, software tools and databases that enabled us to study the dynamics of physiological function mechanistically. Read more.

Structure of the adenosine-bound human adenosine A1 receptor–Gi complex

Comments by Steve Alexander (@mqzspa)

The A1 adenosine receptor is, for most people, a molecular target they can become conscious of when they block it, which happens frequently. Rapid consumption of higher doses of caffeine, in products like Italian espresso or Turkish coffee, provokes a … Read more.

Commentary on the distinction between Cannabis and cannabinoids

Commentary by Steve Alexander (@mqzspa) & Anthony Davenport

The Cannabis plant is a natural product from which more than 100 apparently unique metabolites (cannabinoids) have been identified. Many of these have been found in human plasma following consumption of Cannabis preparations. Read more.

(Update): From double to triple whammy for BACE1 inhibitors

Comments by Chris Southan (@cdsouthan)

19 June 2018 update. Announced only about a week after the events described below,  yet a third clinical candidate, lanabecestat  (AZD-3293, LY3314814) has also bitten the dust (4).  The two PhIII trials were stopped because they were deemed unlikely to meet their primary endpoints. Read more.

Cryo-EM structure of the adenosine A2A receptor coupled to an engineered heterotrimeric G protein

Comments by Steve Alexander (@mqzspa)

The A2A adenosine receptor is densely expressed in dopamine-rich areas of the brain and in the vasculature. It is the target of an adjunct medication for Parkinson’s Disease, istradefylline in Japan, an A2A receptor antagonist. Read more.

Conformational plasticity in the selectivity filter of the TRPV2 ion channel

Comments by Steve Alexander (@mqzspa)

The TRPV2 ion channel is the less well-characterised relative of the TRPV1 or vanilloid receptor that is activated by capsaicin. TRPV2 channels have many similarities to the TRPV1 channels, in that they are homotetrameric and respond to some of the same ligands (natural products such as cannabinoids) as well as being triggered at elevated temperatures. Read more.

3D structure of the P2X3 receptor bound to a negative allosteric modifier, identifies a binding site that is a target for development of novel therapeutic agents

Comments by Dr. Charles Kennedy, University of Strathclyde

Negative allosteric modulators (NAMs) are of great interest in drug development because they offer improved scope for the production of receptor antagonists with enhanced subtype-selectivity. Indeed, many NAMs are already on the market or undergoing clinical trials. NAMs act byRead more.

3D structures of the closed acid-sensing ion channel (ASIC) shed light on the activation mechanism of these neuronal ion channels

Comments by Stephen Kellenberger, Université de Lausanne, Switzerland

ASICs are potential drug targets of interest. Their activation mechanism has however remained elusive. ASICs are neuronal, proton-gated, sodium-permeable channels that are expressed in the central and peripheral nervous system of vertebrates. Read more.

Engineered mini G proteins provide a useful tool for studying the activation of GPCRs in living cells

Comments by Shane C. Wright and Gunnar Schulte, Karolinska Institute

In order to stabilize the GPCR-G protein complex, an agonist must be bound to the receptor and the alpha subunit of the heterotrimer must be in a nucleotide-free state. Read more.

Unexplored therapeutic opportunities in the human genome

Comments by Chris Southan, IUPHAR/BPS Guide to PHARMACOLOGY, @cdsouthan

Contemporary drug discovery is dominated by two related  themes. The first of these is target validation upon which the sustainability of pharmaceutical R&D (in both the commercial and academic sectors) crucially depends. Read more.


Ireland SM, Southan C, Dominguez-Monedero, Harding SD, Sharman JL, Davies JD. (2018). SynPharm: A Guide to PHARMACOLOGY Database Tool for Designing Drug Control into Engineered Proteins. ACS Omega, 3 (7), pp 7993–8002, doi: 10.1021/acsomega.8b00659.

Southan C, Sharman JL, Faccenda E, Pawson AJ, Harding SD, Davies JA. (2018). Challenges of Connecting Chemistry to Pharmacology: Perspectives from Curating the IUPHAR/BPS Guide to PHARMACOLOGY. ACS Omega, 3 (7), pp 8408–8420, doi: 10.1021/acsomega.8b00884.

Davenport AP, Kuc RE, Southan C, Maguire JJ. (2018). New drugs and emerging therapeutic targets in the endothelin signaling pathway and prospects for personalized precision medicine. Physiol. Res., (Suppl. 1): S37-S54, doi: 10.1021/acsomega.8b00659. [PMID:29947527]



Caraci F, Calabrese F, Molteni R, Bartova L, Dold M, Leggio GM, Fabbri C, Mendlewicz J, Racagni G, Kasper S, Riva MA, Drago F. (2018) International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets. Pharmacol Rev. 70: 475-504. [PMID:29884653]

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Posted in Hot Topics

Hot Topics: Direct activation of neuronal KV7 channels by GABA and gabapentin – a novel mechanism for reducing neuronal excitability

The potassium channels KV7.2-KV7.5 (KCNQ2-5; GtoPdb target IDs 561-564) regulate neuronal excitability in the mammalian nervous system. The best characterised neuronal KV7 channels give rise to the M current (1) and are mediated predominantly by hetero-tetramers of KV7.2 and KV7.3 subunits (2). Established anticonvulsant agents such as retigabine are known to dampen neuronal excitability by activating neuronal KV7 channels. A tryptophan in the S5 transmembrane region of neuronal KV7 channels is essential for retigabine sensitivity with KV7.3 channels particularly sensitive. Importantly, this residue is not present in the cardiac KV7.1 (KCNQ1) channel, reducing the potential for cardiac side effects.

Now, a pair of studies (3, 4) has shown that this same region of the channel also contributes to a high affinity binding site for GABA and related metabolites (3). GABA activates channels comprised of KV7.3 and KV7.5, including heteromeric KV7.2/7.3 channels, with high potency but low efficacy. GABA does not, however, activate KV7.2 or KV7.4 homomeric channels or cardiac KV7.1 channels. The synthetic anticonvulsant and antinociceptive agent gabapentin activates the same KV7 subunits, although pregabalin does not, despite the overlapping therapeutic efficacy of these two compounds (4).

These results are of considerable pharmacological interest. They suggest a novel mechanism for GABA in regulating neuronal excitability through activation of KV7 channels. They indicate that both GABA and gabapentin will interfere with the action of therapeutically useful activators of KV7 channels such as retigabine. However, perhaps of most value given the relative difficulty in identifying potassium channel openers compared to blockers (5), this work identifies a new chemical class of potential therapeutic activators of neuronal KV7 channels that target an identified region of these channels.

Comments by Emma L. Veale (@Ve11Emma) and Alistair Mathie (@AlistairMathie)

(1) Brown, D.A. & Adams P.R. (1980). Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone. Nature, 283. 673-676. [PMID: 6965523].

(2) Wang H.S. et al. (1998). KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science, 282. 1890-1893. [PMID: 9836639].

(3) Manville R.W. et al. (2018). Direct neurotransmitter activation of voltage-gated potassium channels. Nature Commun., 9(1). 1847. [PMID: 29748663].

(4) Manville R.W. & Abbott G. (2018). Gabapentin is a potent activator of KCNQ3 and KCNQ5 potassium channels. Mol. Pharmacol., doi: 10.1124/mol.118.112953. [PMID: 30021858].

(5) Liin, S.I. et al. (2018). Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors. J. Gen. Physiol., doi: 10.1085/jgp.201711942. [PMID: 30002162].

Posted in Hot Topics

Hot topic: New pharmacological tools reiterate lack of direct connection between Angiotensin 1–7 and the MAS1 GPCR

A new type of deorphanization conundrum confronted in pairing the GPCR, MAS1 with the hormonal peptide angiotensin 1–7 (Ang1-7) was emphasised in recent IUPHAR reviews (1, 2). More evidence for disconnection between Ang1-7 and MAS1 is presented in the recent paper by Gaidarov et al. (3). Ang1-7 is produced by ACE2 or neutral endopeptidase by cleavage of a single amino acid, phenylalanine 8, from angiotensin II (AngII), the major renin angiotensin system hormone. MAS1 was described as the primary receptor for Ang1-7 in regulating diverse biological activities, including vasodilatory, cardio-protective, antithrombotic, antidiuretic and antifibrotic effects (4). These activities are lost in tissues of MAS1-deficient animals, producing striking phenotypes observed in the cardiovascular, renovascular, nervous and reproductive systems. Vast physiological responses to Ang1-7 studied in MAS1-deficient animals serve as the most compelling argument in favor of Ang1-7 pairing with MAS1. However, support for a direct interaction of Ang1-7 with MAS1 lack demonstration of classical G protein signaling and desensitization response to Ang1-7, as well as a lack consensus on confirmatory molecular pharmacological analyses (1, 2).

MAS1-selective small molecule agonists and antagonists from Arena Pharmaceuticals have aided mechanistic study of signaling dynamics in recombinant MAS1 expressing cells. Gaidarov et al. systematically tested efficacy of MAS1-selective non-peptide agonists and antagonists in GPCR signaling and also in signaling-pathway independent assay platforms [3]. Arena Pharmaceutical’s non-peptide ligands modulated G protein-dependent and independent pathways through MAS1, including Gq and Gi pathways, 35S-GTPɣS binding, β-arrestin recruitment, Erk1/2 and Akt phosphorylation, arachidonic acid release, and receptor internalization. Moreover, non-peptide agonists produced robust responses in dynamic mass redistribution (DMR) assays that provide a pathway-agnostic cellular response. The Ang1-7 peptide obtained from multiple sources was inert. In the cell-free assay for G protein coupled MAS1, 35S-GTPɣS binding was undetected in the presence of Ang1–7 suggesting lack of direct interaction with MAS1.

To reject the in vivo analysis based MAS1 pairing with Ang1-7 would still be premature based on the conclusions of Gaidarov et al. (and similar papers cited in ref. #2). MAS1 pairing with Ang1-7 should be considered in the context of type 1 and type 2 errors originally described by Neyman and Pearson (5) and recently revisited (6). Type 1 errors are experiments causing rejection of a null hypothesis which may be true. Type 2 errors are experiments insufficient to reject a flawed null hypothesis. Experiments need to be designed to test the validity of MAS1 functions modulated in vivo by Arena Pharmaceutical ligands rather than simply failing to find pairing with Ang1-7. Involvement of additional GPCRs as “Ang1-7 receptors” or signalosome mechanisms that can link Ang1-7 with MAS1 deserve consideration (7).

Comments by Sadashiva S. Karnik ( and Kalyan Tirupula


  1. Karnik SS, Singh KD, Tirupula K, Unal H. (2017) Significance of angiotensin 1-7 coupling with MAS1 receptor and other GPCRs to the renin-angiotensin system: IUPHAR Review 22. Br J Pharmacol. 174: 737-753. doi: 10.1111/bph.13742. Review. PMID: 28194766
  2. Karnik SS, Unal H, Kemp JR, Tirupula KC, Eguchi S et al. (2015) International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli [corrected]. Pharmacol Rev 67: 754-819. PMID: 26315714
  3. Gaidarov I, Adams J, Frazer J, Anthony T, Chen X et al. (2018) Angiotensin (1-7) does not interact directly with MAS1, but can potently antagonize signaling from the AT1 receptor. Cell Signal 50: 9-24. PMID: 29928987
  4. Bader M, Alenina N, Andrade-Navarro MA, Santos RA (2014). MAS and its related G protein-coupled receptors, Mrgprs. Pharmacol Rev. 66: 1080–1105. PMID: 25244929
  5. Neyman, J. and Pearson, E.S. (1928). On the use and interpretation of certain test criteria for the purposes of statistical inference. Part I and Part II. Biometrika 20A, 175–240.
  6. Lew MJ (2006). Principles: when there should be no difference–how to fail to reject the null hypothesis. Trends Pharmacol Sci. 27:274-278. PMID: 16595154
  7. Tirupula KC, Zhang D, Osbourne A, Chatterjee A, Desnoyer R, Willard B et al. (2015). MAS C-terminal tail interacting proteins identified by mass spectrometry-based proteomic approach. PLoS One 10: e0140872. PMID: 26484771
Posted in Hot Topics

Hot Topic: Structural details for coupling of the agonist-occupied µ opioid receptor (amongst others) to the Gi protein

Every few years in the field of receptor pharmacology, a technological advance occurs that drives the field forward in terms of insight and understanding. Over the past couple of years, the cryo-EM technique (the development of which won the 2017 Nobel Prize in Chemistry for Dubochet, Frank, and Henderson) for resolving protein structures at near atomic resolution has been highlighted as one such approach. Now some of the first papers applying this methodology to G protein-coupled receptors (GPCRs) are beginning to appear. The strength of this approach for GPCRs is revealed in the recent paper by Koehl et al. (1) showing the detailed structure of the agonist-bound µ opioid receptor (GtoPdb target ID 139) coupled to the Gi subtype of G protein. DAMGO (GtoPdb ligand ID 1647), the agonist used in the study, is a selective and efficacious peptide agonist at the µ receptor and is used in many studies as the standard µ receptor agonist. The structure of the DAMGO-µ receptor-Gi complex shows some interesting and unexpected detail, for example, that the binding pocket for Gi at the base of the receptor is smaller, and the outswing of the lower end of TMD VI smaller, than that for GPCRs that couple primarily to Gs proteins.

Apart from the obvious benefits for future drug development at µ receptor, the full impact of the cryo-EM approach for µ receptor structure/function is likely to be felt more in the future, as we can no doubt look forward to the appearance of µ receptor/signalling protein structures with partial agonists as well as biased agonists, and the structure of ligand-bound µ receptor interacting with GRKs or arrestin proteins. The speed at which this field is moving is already breathtaking – in the issue of Nature carrying the DAMGO-µ receptor-Gi cryo-EM report, there are others detailing the structure of activated rhodopsin-Gi (2), adenosine activated adenosine A1-Gi (3) and agonist-activated 5HT1B-Go (4). Recently also the structure of the Class B GLP-1 receptor in complex with a biased ligand and Gs was reported (5). Many more structures of such complexes are likely to follow over the next couple of years, with a corresponding leap forward in our understanding of the structure and function of GPCRs. There are still challenges however; as Koehl and colleagues point out in their groundbreaking paper (1), the nature of the initial interactions of G proteins and other signalling proteins with GPCRs, and the identity of the possibly novel receptor conformations that exist at these early time points in complex formation, remain considerable challenges for both X-ray crystallography and cryo-EM techniques.

Comments by Eamonn Kelly ( and Katy Sutcliffe

(1) Koehl A. et al. (2018). Structure of the μ-opioid receptor–Gi protein complex. Nature, 558. 547–552. [PMID: 29899455]

(2) Kang Y. et al. (2018). Cryo-EM structure of human rhodopsin bound to an inhibitory G protein. Nature, 558. 553-558. [PMID: 29899450]

(3) Draper-Joyce C.J. et al. (2018). Structure of the adenosine-bound human adenosine A1 receptor–Gi complex. Nature, 558. 559–563. [PMID: 29925945]

(4) García-Nafría J. et al. (2018). Cryo-EM structure of the serotonin 5-HT1B receptor coupled to heterotrimeric Go. Nature, 558. 620-623. [PMID: 29925951]

(5) Liang Y.L. et al. (2018). Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature, 555. 121-125. [PMID: 29466332]

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Posted in Hot Topics

Hot Topic: Systems Medicine, Disease Maps and the future of Systems Biology

What will Systems Biology look like in the future? Up to now, it has focussed on the development of standards, software tools and databases that enabled us to study the dynamics of physiological function mechanistically. However as these tools and technologies have matured, the focus of the systems biology research community has moved towards how they can best be interconnected and exploited to develop our understanding of health and disease across whole cells, tissues, organs, organisms. This version 2.0 of systems biology, will build on the existing technologies to create resources that are more intuitive, more accurate, more accessible and are easier to use for anyone engaged with research.

Disease maps describe the interactions and pathways that are perturbed from healthy physiological function in disease pathophysiology. The Disease Maps consortia, spearheaded by the Luxembourg Centre for Systems Biomedicine, the Institut Curie and the European Institute for Systems Biology and Medicine, are developing rich resources to enable us to understand how healthy function is perturbed across different scales. These include from the molecular to the organismal, and that embed individually perturbed pathways in a wider intra- and inter-cellular network so that the systems and systemic impact can be more easily investigated [1].   Each disease topic is the focus of a community of clinical, laboratory and systems biology expertise and the consortia is organised as a community of communities with the following adopted principles:-

  • Central integration of in vivo and in vitro disease experts across diseases
  • Close integration of pathway mapping and modeling expertise
  • Regular sharing of best practice and expertise across diseases

The consortia embrace open access, standard formats, modularity, consistency of quality and best practices in the field. It is anticipated that this work will deliver resources that can support comprehensive programmes of systems medicine by including the following:

  • Dedicated trusted reference resources describing disease mechanisms that facilitate advanced data interpretation, hypothesis generation, and hypothesis prioritisation.
  • Tools for the study of co- and multi-morbidities, which can deliver refined biomarkers for improved clinical diagnostics.
  • Tools for the study of systems pharmacology that suggest drug repositioning and multi-drug intervention strategies.
  • Novel insights into disease subclassification supporting the development of next-generation disease ontologies.
  • Supporting the design and prototyping of new clinical decision-making strategies.

The Disease Maps consortia thus want to accelerate the development of Systems Biology 2.0 and the roadmap presented in this paper describes how it can be steered towards translational utility.

Comments by Steven Watterson (@systemsbiology), University of Ulster

[1]. Mazein A, Ostaszewski M, Kuperstein I, Watterson S, Le Novère N, Lefaudeux D, De Meulder B, Pellet J, Balaur I, Saqi M, Nogueira MM, He F, Parton A, Lemonnier N, Gawron P, Gebel S, Hainaut P, Ollert M, Dogrusoz U, Barillot E, Zinovyev A, Schneider R, Balling R and Auffray C (2018) Systems medicine disease maps: community-driven comprehensive representation of disease mechanisms, NPG Systems Biology and Applications 4:21. [PMID 29872544]

Posted in Hot Topics

Hot topic: Structure of the adenosine-bound human adenosine A1 receptor–Gi complex

The A1 adenosine receptor is, for most people, a molecular target they can become conscious of when they block it, which happens frequently. Rapid consumption of higher doses of caffeine, in products like Italian espresso or Turkish coffee, provokes a rapid, transient increase in heart rate and a noticeable increase in limb tremor. As the most widely consumed psychoactive substance, caffeine has these effects through blockade of the A1 adenosine receptor, which is found on cardiomyocytes and the peripheral nerve terminals of the sympathetic nervous system (as well as many other locations), leading to an increase in cardiac contractility and noradrenaline release, respectively.

In this report, a 3.6 Å structure of the receptor complexed with the endogenous agonist, adenosine, in the presence of the heterotrimeric G12 protein has been resolved by cryo-EM. As expected, there are differences in conformation compared to the previously-reported antagonist-bound receptor, principally in TM1 and TM2. There are also differences compared to the structure reported for the Gs-coupled, agonist-bound beta2-adrenoceptor.

Comments by Steve Alexander (@mqzspa)

(1) Draper-Joyce C.J. et al. (2018). Structure of the adenosine-bound human adenosine A1 receptor–Gi complex. Nature, 558. 559–563. [PMID: 29925945]

Posted in Hot Topics

Database release 2018.3

Our third database release of the year, 2018.3, is now available. This update contains the following new features and content changes:

Content updates

Adenosine receptors
Chemokine receptors
Cholecystokinin receptors
Dopamine receptors
Ghrelin receptors
Opioid receptors
GPR55 receptors

MRetinoic acid receptor

Transient Receptor Potential channels
voltage-gated sodium channels

Guanylyl cyclases (GCs)
Janus kinase (JakA) family
Mitogen-activated protein kinases (MAP kinases)
Nitric oxide synthases

Catalytic Receptors:
Natriuretic peptide receptor family

ABCG subfamily
Monoamine transporter subfamily

CD molecules

Anti-malarial data

The existing Antimalarial targets family has been updated with 5 new P. falciparum (3D7) targets:

  • PfATP4 (Plasmodium falciparum ATPase4)
  • PfDHFR-TS (Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase)
  • PfDXR (Plasmodium falciparum 1-deoxy-D-xylulose 5-phosphate reductoisomerase)
  • PfeEF2 (Plasmodium falciparum elongation factor 2)
  • PfPI4K (Plasmodium falciparum phosphatidylinositol 4-kinase)

A new Antimalarial ligands family has been created and contains 30 ligands all tagged as an antimalarial in the database. Of these 30, 20 are new ligands curated for this release.

New website features

GtoImmuPdb now public

The IUPHAR Guide to IMMUNOPHARMACOLOGY is now at its first public release and is no longer considered a beta version. We will continue to develop the portal and specific immuno interfaces as well as continuing curation towards its official launch in October 2018. This will be at the BPS Immunopharmacology: Challenges, opportunities and research tools meeting in Edinburgh, 1st-2nd October 2018.

Disease Summary Pages

The disease summary pages have been modified to improve the payout of target information and provide links to help to understand terms and symbols. The display of associated ligand is now in a sortable table and the comments section includes bioactivity comments where present. We have also include links to the specific clinical data or bio-activity tabs on ligand summary pages.

Posted in Database updates, Guide to Immunopharmacology, Guide to Malaria Pharmacology

Commentary on the distinction between Cannabis and cannabinoids

The Cannabis plant is a natural product from which more than 100 apparently unique metabolites (cannabinoids) have been identified. Many of these have been found in human plasma following consumption of Cannabis preparations. The most well-recognised is tetrahydrocannabinol, THC, because of its well-documented psychotropic effects mediated through activating CB1 cannabinoid receptors. It has been used clinically as an anti-emetic and for treating glaucoma.

Cannabidiol, CBD, is also a prominent metabolite from the plant, which lacks the psychotropic effects of THC, since it is not an agonist at CB1 cannabinoid receptors. It is in advanced trials for treating childhood epilepsy, but may also have benefit in schizophrenia or post-traumatic stress disorder. The molecular mechanisms of action of CBD are not precisely defined, but may involve multiple targets.

A standardised combination of THC and CBD is available in many countries, including the UK as a licensed medicine for treating the symptoms of multiple sclerosis.

There is a lack of clear understanding of the biological effects of the majority of the other cannabinoid metabolites from the plant, which may have applications in inflammatory disorders, nausea and metabolic disorders, such as type II diabetes.

In many countries, Cannabis itself is licensed as a medicine for indications such as pain relief or the weight loss associated with terminal cancer or AIDS. However, preparations from Cannabis are highly variable in terms of the spectrum and concentrations of cannabinoid content, as well as other compounds present in the plant, such as the terpenoids, which have also been proposed to have independent bioactivity.

Commentary by Steve Alexander (@mqzspa) & Anthony Davenport

Posted in Hot Topics, Uncategorized

GtoPdb: Database Status Reports

As some of our contacts may know, we hold hemi-annual meetings between IUPHAR, BPS the GtoPdb team, together with invited guests from our collaborators and NC-IUPHAR committee representatives. Covering ~ 2.5 days these usually take place in Paris or Edinburgh. One of the outputs from these rewarding gatherings is an extensive (i.e. ~ 20-25 pages) database report document. For interested parties these provide a usefully detailed snapshot of what we have collectively been up to for the preceding 6-month period.

The last three of these are now on-line (

The latest one (May 2018) also includes links to slide sets shown in the meeting that accompany the report, which are also available here:

Database Status Report: Core GtoPdb

Database Status Report: GtoImmuPdb

Linking GtoPdb, PubChem and PubMed


Posted in Database updates, Technical, Uncategorized

Hot topic (update): from double to triple whammy for BACE1 inhibitors

19 June 2018 update. Announced only about a week after the events described below,  yet a third clinical candidate, lanabecestat  (AZD-3293, LY3314814) has also bitten the dust (4).  The two PhIII trials were stopped because they were deemed unlikely to meet their primary endpoints. This bad news engendered yet another “In The Pipeline” commentary  If detailed reports are eventually published these will be curated as new references for the ligand entry.


BACE1  (beta secretase 1, BACE-1 or BACE) has been a key target for Alzheimer’s disease (AD) for nearly two decades (1).  However, there was a major disappointment when the Phase III trials with the Merck inhibitor verubecestat failed unequivocally despite lowering A-beta levels.  The termination is reported both in NCT01739348  and the  May 2018  full paper on the trial results (2).  The gravity of this setback is underlined by the “In The Pipeline” commentary title “Merck’s BACE-Inhibitor Alzheimer’s Wipeout” wherein it is suggested that this brings the validation status of this target and, by definition, other inhibitors in late-stage development into doubt.  Thus, even glimmers of success for any mechanistic class of AD  therapy would seem to be currently extinguished.   There remains perhaps the slimmest of hopes from the recent report that the initial process of plaque formation might yet prove sensitive to therapeutic BACE1 inhibition (3).  However, there may be no diagnostic and/or biomarker specific enough to identify prospective asymptomatic patients this early in disease development.

The bad news for BACE1 inhibitors was compounded by a press release from Janssen in the same month. They reported serious liver enzyme elevations for some participants in Janssen’s atabecestat  (JNJ-54861911) Phase 2b/3 trial.  While this may be a chemotype liability for this series rather than a target-related issue, it does mean that yet another AD drug candidate has bitten the dust.  We would hope that a full clinical data report on this trial cessation could be pending,  However,  despite a number of early clinical reports, Janssen has not so far published any primary in vitro medicinal chemistry papers on this compound.  Comments about both these failures have also just  appeared in Nature Reviews in Drug Discovery

N.b. Our BACE1  target entry is in the process of being updated so a number of new inhibitors and curatorial comments will appear in database release 2018.3.  The technicalities of gathering these new structures, including unblinding JNJ-54861911, as well as what might still be progressing,  are described in this blog post.

Comments by Chris Southan (@cdsouthan)

1) Southan and Hancock  (2013) A tale of two drug targets: the evolutionary history of BACE1 and BACE2. Front Genet. Dec 17;4:293. doi: 10.3389/fgene.2013.00293.[PMID 24381583]

2) Egan et. al.  (2018)  Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease. N. Engl. J. Med., 378 (18): 1691-1703, [PMID 29719179]

3) Peters et. al. (2018) BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology, Acta Neuropathol. May;135(5):695-710. doi: 10.1007/s00401-017-1804-9. [PMID 29327084]

4) Update on Phase 3 Clinical Trials of Lanabecestat for Alzheimer’s Disease (2918)  Eli Lilly and AstraZeneca press release [CUL 14602932]

Posted in Hot Topics

Database release 2018.2

Our second database release of the year, 2018.2, is now available. This update contains the following new features and content changes:

Content updates

5-Hydroxytryptamine receptors
Adenosine receptors
Histamine receptors
Opioid receptors
Lysophospholipid (S1P) receptors
Prostanoid receptors

Mineralocorticoid receptor
Peroxisome proliferator-activated receptors

Transient Receptor Potential channels

Nitric oxide synthases
Phosphodiesterases, 3′,5′-cyclic nucleotide (PDEs)
Cyclin-dependent kinase (CDK) family
Mitogen-activated protein kinases (MAP kinases)
NADPH oxidases

Monoamine transporter subfamily

Heat shock proteins

New website features

Pharmacology Search Tool

In release 2018.1 we announced a new Pharmacology Search Tool allowing users to upload lists of target ids and find ligands to modulate them. We have now extended this tool to (optionally) search for other relevant ligands in ChEMBL v23. The ChEMBL data has been filtered according to the same rules we use for the ligand activity visualisation charts (see the help documentation for details) and as well as displaying the ChEMBL curated activity values, we also display their calculated -log pChEMBL value. An example of the results returned from this type of search is shown in Fig 1.


Figure 1. Example of results returned from a UniProt Accession search in the Pharmacology Search Tool, showing the top 3 GtoPdb and ChEMBL ligands. Results are ordered by total number of ligands in these databases that match search criteria.

New PDB ligand icon

As part of our increased emphasis on ligand structures (as seen with our synPHARM resource), we have introduced a new ligand icon for PDB entries. We display this on the ligand list and target interaction tables to indicate which ligands have PDB entries (orange circle with a white alpha helix across the centre), as shown in Fig 2.


Figure 2A. The ligand list showing the new PDB ligand icon in orange.


Figure 2B. A target inhibitor table showing the new PDB ligand icon in orange.

Sponsored Tocris product links

We have collaborated with Tocris as a quality supplier of many of the ligands in GtoPdb by adding links from our ligand pages out to the matching Tocris products. An example, which can be found on the ligand page beneath the summary tab, is shown in Fig 3. In total there are links to 1198 Tocris products.


Figure 3. Ligand summary page showing a link to the Tocris product.

Other updates

BJP/BJCP linking

As an adjunct to our successful entity-linking initiative for the BJP and more recently BJCP, we have instigated a process whereby, on manuscript acceptance and their own marking-up of GtoPdb links, authors alert us directly to key entities from their studies that are not in our database. In most cases, we then add the missing ligands. This has the advantages for both the author and the journal of not only adding their reference into GtoPdb but also the paper gains PubChem PubMed reciprocal linking derived from our PubChem ligand submissions. Examples from this release include GS-458967 from BJP and esaxerenone from BJCP.

BACE1 in doubt as an Alzheimer’s drug target

The target entry for the Alzheimer’s drug target BACE1 underwent key updates. The first of these was to add a new reference for the full report published just last week on the Phase III failure of the lead Merck BACE1 inhibitor verubecestat. Unfortunately, this paper now casts doubt on the target validation status and thus the future for this entire class of compounds pursued intensively for over 18 years. Notwithstanding, several ligands on the BACE1 list may yet complete their clinical evaluation (these will be joined by the latest  development candidate from Pfizer as PF-06751979 in 2018.3)

SynPHARM article

We are pleased to report that an open pre-print version (i.e. pending changes compared to the eventually accepted journal version) of our manuscript describing our SynPharm resource is now on-line.


We are also pleased to report the publication of  Accessing Expert‐Curated Pharmacological Data in the IUPHAR/BPS Guide to PHARMACOLOGY. It is not indexed in PubMed yet but note that the PDF is free to access until the end of May (so pull it down while you can! – but we could send you one if you miss the window).  It includes useful examples of how to use both GtoPdb and GtoImmuPdb as a supplement to our online help and FAQ.

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Posted in Database updates, Guide to Malaria Pharmacology

Hot topic: Cryo-EM structure of the adenosine A2A receptor coupled to an engineered heterotrimeric G protein

The A2A adenosine receptor is densely expressed in dopamine-rich areas of the brain and in the vasculature. It is the target of an adjunct medication for Parkinson’s Disease, istradefylline in Japan, an A2A receptor antagonist.

The A2A adenosine receptor is an example of a Gs-coupled receptor, activation of which in the cardiovascular system leads to inhibition of platelet aggregation and vasorelaxation. This new report (1) highlights the link between the receptor and the G protein to focus on areas of unexpected flexibility in the ligand binding region. Further, classical understanding of receptor:G protein interaction identifies a prominent role for the third intracellular loop and the proximal end of the C-terminus (in some GPCR, such as the beta2-AR, a fourth intracellular loop is formed by palmitoylation of an intracellular cysteine residue, which the A2A lacks). The model generated from this cryo-EM study with a nanobody suggests a potentially novel role for an interaction between the first intracellular loop and the Gbeta subunit.

Comments by Steve Alexander (@mqzspa)

(1) Garcia-Nafría J et al. (2018). Cryo-EM structure of the adenosine A2A receptor coupled to an engineered heterotrimeric G protein. eLife, 7. pii: e35946. doi: 10.7554/eLife.35946. [PMID: 29726815]

Posted in Hot Topics

Hot topic: Conformational plasticity in the selectivity filter of the TRPV2 ion channel

The TRPV2 ion channel is the less well-characterised relative of the TRPV1 or vanilloid receptor that is activated by capsaicin. TRPV2 channels have many similarities to the TRPV1 channels, in that they are homotetrameric and respond to some of the same ligands (natural products such as cannabinoids) as well as being triggered at elevated temperatures. This study (1) focusses on a different common feature of the whole Transient Receptor Potential family, which are often described as non-selective cation channels. Using comparative analysis of crystals structures in which calcium is bound with and without an agonist, resiniferatoxin, present. The authors suggest that this agonist evokes a symmetrical opening of a selectivity filter gate, which permits increased permeation of calcium ions and also larger organic cations, such as the dye Yo-PRO-1.

Comments by Steve Alexander (@mqzspa)

(1) Zubcevic L et al. (2018). Conformational plasticity in the selectivity filter of the TRPV2 ion channel. Nat Struc Mol Biol., 25:405-415. doi:10.1038/s41594-018-0059-z. [Abstract]

Posted in Hot Topics

Hot topic: 3D structure of the P2X3 receptor bound to a negative allosteric modifier, identifies a binding site that is a target for development of novel therapeutic agents

Negative allosteric modulators (NAMs) are of great interest in drug development because they offer improved scope for the production of receptor antagonists with enhanced subtype-selectivity. Indeed, many NAMs are already on the market or undergoing clinical trials. NAMs act by binding to sites within receptors that are distinct from the primary, orthosteric ligand binding site and can inhibit the structural rearrangements of a receptor that are induced by orthosteric agonist binding.

P2X receptors are ligand-gated cation channels for which ATP is the endogenous orthosteric agonist. They are expressed throughout the body and the evidence indicates that they have numerous functions, including in sympathetic and parasympathetic neurotransmission, perception of sound, taste and pain, and immune regulation. Seven P2X subunits have been identified, which form trimers, to produce at least twelve different receptor subtypes. A major issue within the field has been a lack of selective antagonists for most P2X subtypes. This is unsurprising given the amino acid sequence similarity within the ATP binding site. Several selective NAMs have now been developed, but little is known about where in receptors they act and how exactly they inhibit receptor activation.

AF-219 is small molecule NAM at P2X3 receptors that was reported to be effective in a phase II clinical trial for treatment of refractory chronic cough. Wang et al., (1) combined X-ray crystallography, molecular modelling, and mutagenesis, to identify the site and mode of action of AF-219. P2X3 receptors are composed of three subunits, each of which adopts a conformation that could be likened to the shape of a leaping dolphin. The tail represents the transmembrane-spanning regions, the upper body the bulk of the extracellular loop and the head the most distal part of the extracellular loop. Also attached to the body are three structurally-distinct elements: the dorsal fin, the right flipper, and the left flipper. As a trimer, the subunits wrap round each other to produce a structure that resembles a chalice.

The AF-219 binding site is formed by the lower body and dorsal fin of one subunit and the lower body and left flipper of an adjacent subunit. Mutational analysis identified which amino acid residues within this pocket are essential for AF-219 binding, whilst in silico modelling showed that the small molecule P2X3 NAMS, AF-353, RO-51, RO-3 and TCP 262, but not the large NAMS suramin and PPADS, also bind to the same site. Activation of P2X3 receptors by ATP closes the binding cavity, so by occupying it, AF-219 prevents the protein structural rearrangements that lead to opening of the P2X3 receptor ion pore.

This identification of the AF-219 NAM binding site in P2X3 receptors is an opportunity for rational, intelligent drug design. It enables virtual screening of compound libraries, with the aim of identifying potential new molecular core structures, which can then be modified in order to optimise the structure of a novel NAM. In addition, this site differs among P2X receptor subtypes, so it is highly possible that drugs with greatly enhanced subtype-selectivity can be developed.

Comments by Dr. Charles Kennedy, University of Strathclyde

(1) Wang J, Wang Y, Cui WW, Huang Y, Yang Y, Liu Y, Zhao WS, Cheng XY, Sun WS, Cao P, Zhu MX, Wang R, Hattori M, Yu Y. (2018). Druggable negative allosteric site of P2X3 receptors. Proc Natl Acad Sci U S A. 2018 pii: 201800907. doi: 10.1073/pnas.1800907115. [PMID:  29674445]

Posted in Hot Topics

Hot topic: 3D structures of the closed acid-sensing ion channel (ASIC) shed light on the activation mechanism of these neuronal ion channels

ASICs are potential drug targets of interest. Their activation mechanism has however remained elusive. ASICs are neuronal, proton-gated, sodium-permeable channels that are expressed in the central and peripheral nervous system of vertebrates. They form a subfamily of the Epithelial Na channel / degenerin channel family, and contribute to pain sensation, fear, learning, and neurodegeneration after ischemic stroke. Depending on the extracellular pH, they exist in either one of three functional states: closed (resting), open and desensitized. While ASICs are at physiological pH 7.4 in the closed state, they open briefly upon extracellular acidification, before entering the non-conducting desensitized state. Crystal structures of the chicken ASIC1 channel in the desensitized and the open state were published several years ago. This structural information allowed, together with observations from functional studies, an understanding of the transitions between the open and the desensitized state. In contrast, the absence of structural information on the closed conformation of ASICs precluded so far a molecular understanding of their activation mechanism.

The Gouaux laboratory has now published structures of the homotrimeric chicken ASIC1 obtained at high pH by X-ray crystallography (2.95 Å resolution) and by single particle cryo-electron microscopy (3.7 Å) (1). These structures show a channel with a closed pore, representing likely the closed state. The overall structural organization is the same in all ASIC 3D structures published so far: each subunit consists of a large, complex ectodomain, two transmembrane domains, and short N- and C-termini (whose structure has not been resolved yet). The channel is formed by three identical subunits that are arranged around the central ion pore. A vestibule containing many acidic residues, the “acidic pocket”, is located on the outward-facing side of the ectodomain of each subunit, at 40-50 Å from the membrane. The main difference in the ectodomain between the closed ASIC structures and previously published open and desensitized structures is a wide opening of the acidic pocket in the structure of the closed channel.

Based on the comparison of closed, open and desensitized structures, the authors suggest the following activation mechanism: At physiological pH 7.4 the channel pore is closed and the acidic pocket has adapted an extended conformation. Extracellular acidification protonates acidic residues of the acidic pocket, thereby reducing repulsion between such residues and leading to a collapse of the acidic pocket. This movement is transmitted via central channel domains to the transmembrane helices, and leads to opening of the channel pore. A short time later, an additional movement in the central domains uncouples the ion pore from the acidic pocket and allows the transmembrane domains to relax to the non-conducting desensitized conformation. The acidic pocket will adapt its extended conformation only once the extracellular pH has returned to higher values.

This new 3D structure is undoubtedly a breakthrough in the understanding of the molecular mechanisms of ASIC activity. Some open questions remain however:

Several studies have shown that protonation events in domains other than the acidic pocket contribute to activation and desensitization, and it has also been shown that a channel in which most of the acidic residues in the acidic pocket have been neutralized can still be opened by extracellular acidification. These studies suggest that an important part of the drive for the conformational changes comes from protonation events outside the acidic pocket. This is different from the activation mechanism proposed by Yoder and colleagues, which relies on protonation events in the acidic pocket.

The cytoplasmic N- and C-termini of ASIC subunits contain sites important for ASIC function and ion selectivity. So far there is no structural information on these intracellular parts available. Future cryo-electron microscopy approaches will hopefully have the power to resolve the conformation of these domains.

Comments by Stephan Kellenberger, Université de Lausanne, Switzerland

1. Yoder, N., Yoshioka, C., and Gouaux, E. (2018) Gating mechanisms of acid-sensing ion channels. Nature, 555: 397-401. doi: 10.1038/nature25782. [PMID:29513651]

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Posted in Hot Topics

Hot topic: Engineered mini G proteins provide a useful tool for studying the activation of GPCRs in living cells

In order to stabilize the GPCR-G protein complex, an agonist must be bound to the receptor and the alpha subunit of the heterotrimer must be in a nucleotide-free state. Ground-breaking work by expert crystallographers made use of so-called mini G (mG) proteins to stabilize the active conformation of the adenosine A2A receptor in the presence of agonist and guanine nucleotides, but in the absence of Gβγ [1]. These engineered G proteins behave in a way that mimics the nucleotide-free state despite being bound to GDP; thus, they can be seen as conformational sensors of the active receptor state. This work paved the way for another study recently published in the Journal of Biological Chemistry led by Nevin A. Lambert that looked to build on this minimalistic approach to see if representative mG proteins from the four subclasses (Gs, Gi/o, Gq/11 and G12/13) could 1) detect active GPCRs and 2) retain coupling specificity [2]. Using bioluminescence resonance energy transfer (BRET) assays, the interaction between mGs, mGsi, mGsq or mG12 with prototypical GPCRs was quantified to examine whether these tools could reveal ligand efficacy/potency and G protein specificity. This was not only confirmed through exhaustive validation, but surprisingly uncovered secondary coupling interactions that might be of potential interest for follow-up studies. The GPCR superfamily comprises more than 800 GPCRs – most of which we know very little about. These elegant tools should prove valuable in increasing our knowledge about the lesser known GPCRs as well as allow for the discovery of G protein subtype-biased ligands and for unravelling receptor coupling complexity.

Comments by Shane C. Wright and Gunnar Schulte, Karolinska Institute


  1. Carpenter B, Nehme R, Warne T, Leslie AG and Tate CG. (2016) Structure of the adenosine A(2A) receptor bound to an engineered G protein. Nature, 536 (7614): 104-107. [PMID:27462812]
  2. Wan Q, Okashah N, Inoue A, Nehme R, Carpenter B, Tate CG and Lambert NA. (2018) Mini G protein probes for active G protein-coupled receptors (GPCRs) in live cells. J Biol Chem. pii: jbc.RA118.001975. doi: 10.1074/jbc.RA118.001975. [Epub ahead of print] [PMID:29523687]
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Hot Topic: Unexplored therapeutic opportunities in the human genome

Contemporary drug discovery is dominated by two related  themes. The first of these is target validation upon which the sustainability of pharmaceutical R&D (in both the commercial and academic sectors) crucially depends.  The second is the size of the pool of human proteins that are/could become tractable to being progressed towards clinical efficacy as their final validation step (otherwise known as the druggable proteome).  This usefully detailed review, by a large team of authors, touches on both themes but with a focus on how the community might increase the target pool by data-driven knowledge expansion for hitherto less well characterised proteins [1].

As explained in the paper, this shortfall is being addressed by the NIH Illuminating the Druggable Genome (IDG) project since 2014 [2].  As essential reading for those engaging with the  intersects between pharmacology and drug discovery, just a few aspects can be picked out. One of these is their formalisation of a target development level (TDL) classification scheme of Tclin (clinical evidence), Tchem (chemical modulators), Tbio (biological data)  and Tdark related to the depth of investigation.  This “dark” category encompasses proteins with the least current knowledge (i.e. unvalidated potential targets) and a low number of (if  any) molecular probes.  Included in this are of course the orphan GPCRs that have been the subject of previous Hot Topics in their own right [3].

The authors not only point to many additional resources but also present a wealth of detailed statistics on many aspects of drug targets.  These included (Table 1) that eight olfactory receptors have Tbio level data.  Another nugget was the fact that phenomenological responses following radiation therapy is a bona fide biological functional characterisation approach that few of us are aware of. Last but not least, we were pleased to see GtoPdb [4] cited as one of the sources included in this impressive analysis.

For the record, our own curatorially-supported human druggable target list encompasses 1496 proteins with quantitative ligand interactions.  This can be found via the UniProt cross-reference. (n.b. this number will change slightly as the links from our own latest database release will update in the forthcoming UniProt release).

Comments by Chris Southan, IUPHAR/BPS Guide to PHARMACOLOGY, @cdsouthan
  1. Oprea TI et al. (2018). Unexplored therapeutic opportunities in the human genome. Nat Rev Drug Discov. doi: 10.1038/nrd.2018.14 [Epub ahead of print] [PMID:29472638]
  2. Illuminating the Druggable Genome (IDG) Program.
  3. Hot topic: The G Protein-Coupled Receptors deorphanization landscape.
  4. Southan C et al. (2016) The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands.  Nucleic Acids Res. 44(D1):D1054-68. doi: 10.1093/nar/gkv1037. [PMID:26464438]


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GtoImmuPdb: technical update March 2018 – beta-release v3

We are pleased to announce the third, beta-release of the Wellcome Trust-funded IUPHAR Guide to IMMUNOPHARMACOLOGY (GtoImmuPdb). Since our last release in August 2017 we have implemented developments that include disease summary pages, graphical browsing features and extensions and improvements to the advanced search. This blog-post details the major developments in the v3.0 release. This release coincides with the latest 2018.1 GtoPdb release.

Portal layout (

Some minor adjustments have been made to the portal with the social media feed panel switching to the right-hand column, updated news items included and changes to support navigation to the new disease page from the disease panel and from a new ‘Diseases’ menu bar item.


GtoImmuPdb beta v3.0 portal.

Disease associations and display

A major new development has been changes to the way disease associations are presented. Previously, we had listed diseases associated to targets and diseases associated to ligands separately. It made sense to consolidate these into a single list of diseases and then to provide specific disease summary pages where all curated information about a disease could be presented. This work was done in conjunction with the Guide to PHARMACOLOGY (GtoPdb) development, as GtoPdb already contains information on target pathophysiology and mutations relating to specific diseases.


New disease list page. Show alphabetical list of disease, with synonyms and count of associate targets and ligands.

The new disease list page, accessed from the new menu-bar item, lists all diseases with curated data in GtoPdb/GtoImmuPdb. A convenient alphabetical list of diseases, with links to the disease summary pages, synonyms and counts of associated targets and ligands.  Our longer-term aim is to provide several disease categories, but currently only two (selected from a tab at the top) can be viewed; all diseases and immuno disease. The immuno diseases category are diseases that have data curated specifically as part of GtoImmuPdb. These are diseases that are relevant to immunology, and/or are associated to targets and ligands of immunological-relevance.

The disease summery pages have been designed to display all pathophysiology, mutation and immunopharmacology data curated in GtoPdb and GtoImmuPdb in one place. See the disease summary for Psoriasis.

General information about the disease is shown, including synonyms, descriptions, links to external disease resources (OMIM, Orphanet, Disease Ontology) and counts of the total associated targets and ligands, alongside whether there is data of immuno-relevance.


Disease summary page for Psoriasis. Top section give overview of disease, including description, synonyms and links. Counts of associated targets and ligands are shown, along with whether the disease is immune relevant.

The detailed information on each target gives a summary of any curated pathophysiology data, including the role of the target along with information on drugs and their therapeutic use and side effects. If any mutation data is available this is indicated, with links back to the relevant section of the targets detail view page. The target information also shows any specific immunopharmacology comments and ligands for which their is interaction data where the ligand is also associated with the disease.


Detailed target and ligand sections of the disease summary pages (here showing for Psoriasis).

The ligand section is currently populated with data only curated through he GtoImmuPdb project. Included is information on whether the ligand is an approved drug, immunopharmacology comments and clinical use information.

Graphical browsing (Cell types)

GtoImmuPdb has been exploring different ways for users to explore and browse data, one of which is via the use of graphics and images. We took an tree diagram of immune system cell types from Wikimedia Commons and adapted it to show the cell types for which we have data. The image was re-labelled and an image map produced to make it interactive and a way to browse to different data types.


New graphical browsing of cell types implemented in GtoImmuPdb (

Advanced Search

The search facility has been extended to cover disease, processes and cell types. This has included ensuring that search on Cell and Gene Ontology terms work by inference. For example a search on ‘cytokine’ will match a GO parent term that contains the word ‘cytokine’ and bring back targets annotated to that term, or any of it’s children.

All immunopharmacology fields (comments, top-level categories, ontology terms, ontology IDs) have now been added to the advanced search for both targets and ligands – so searches can be restricted to these fields.


New immuno feature incorporated into the advanced search

Process Associations – GO evidence display

We have adjusted the display of GO terms in both Process Association to Target pages and the target detailed view pages. On the target detailed view page, the section on process associations only show GO term associated to the target if the have GO evidence other than ‘IEA’  (inferred by electronic annotation).  The IEA evidence is the only evidence used by GO that “is assigned by automated methods, without curatorial judgement”. As such we hide these by default (but users can expand the section to see them). On the process association page, the IEA terms are show, but italicised, to emphasise this difference.


Modifications to show/hide GO associations with IEA evidence.


To reflect the changes made in this release our help pages have been updated (, and we intended to follow this up by putting in place in-line pop-up help, help videos and a revised tutorial.

This project is supported by a 3-year grant awarded to Professor Jamie Davies at the University of Edinburgh by the Wellcome Trust (WT).

Posted in Guide to Immunopharmacology, Technical

Database release 2018.1

Pharmacology Search results table
The first GtoPdb and GtoImmuPdb beta release of  2018 includes plenty of target and ligand updates as well as announcing some important new features.
As always, full content statistics for release 2018.1 can be found on the database about page.

New website features

Disease listing and disease pages

For the first time, disease information has been gathered together in one place, under a new menu bar option called “Diseases”, which links to a full listing of all the diseases described in GtoPdb. In addition, an “Immuno disease” tab links to a listing of diseases that are relevant to immunology and linked to targets and ligands in GtoImmuPdb.

The table includes the number of targets and ligands that have been associated with the disease by our curators (note, so far only the relationships between ligands relevant to immunological diseases have been formalised in the database structure, so many diseases are not yet linked up to relevant ligands/drugs).
Individual disease pages include information about the disease, such as synonyms and links to Disease Ontology, OMIM or Orphanet where available.
Targets and ligands linked to the disease are listed, with information on disease-causing mutations if known. As noted above, currently the only ligands that have been formally associated with diseases cover the immunopharmacology domain, but we hope to extend this in the future. For further details see the help documentation.
The GtoPdb disease listing

The image shows part of the full disease list. The immunologically-relevant diseases are also shown under a dedicated tab.

Disease list and disease summary pages

Showing a disease summary page with links to external resources and listing the associated targets and ligands in GtoPdb/GtoImmuPdb.

Pharmacology search tool

The new Pharmacology search tool and browser can be found under the Advanced search drop-down menu. This tool allows users to upload target ID sets to retrieve a list of ligands which modulate those targets. Detailed information on how to use it can be found in the help page. After uploading a list of IDs (e.g. UniProtKB accessions or Ensembl gene IDs), select the number of interactions to show, and optionally, the species for the target of the interaction. By default, the results will show the top 5 interactions ordered by decreasing affinity. On the results page, the targets are ordered by how many interactions they have that match the search criteria, with 10 targets per page. A more detailed table of results (including ligand structures and affinity values) is available to download as a CSV file by clicking the “Download” button at the top of the page.
Pharmacology Search results table

Showing a section of the results page following a Pharmacology Search. The default search returns the top 5 interactions for each target.

We’ll be extending the functionality of the tool over the next few months, so please send us your feedback and bug reports to the usual email address!

Target updates

These are some of the targets which have been updated in the new release.


GPR35 (Class A Orphans)
ACKR3 (Chemokine receptors)

Ion channels


ATP-binding cassette transporter family
SLC22 family of organic cation and anion transporters


An update has brought our BACE1 lead inhibitors collection up to 20 with the addition of elenbecestat (E2609) and RO5508887 as clinical candidates, NB-360 with a good brain penetration and Compound 12 [PMID:28626832] as an interesting precedent of a fragment with a PDB structure.  Some of these also have approximate equipotency against with BACE2. Since nearly all BACE1 inhibitors have failed clinically over the last decade (with the Merck verubecestat even having abandoned the prodromal arm) the prospects for this mechanism of action look so bleak as to challenge the central hypothesis of APP secretase target validation.  Our entries now give research groups the option of direct mouse model translational comparisons between these leads in the hope of providing at least some insight into failures and possible progress.

Other new data

From time to time we select entries from relatively new journals that are including quality pharmacology papers.  This release includes two examples. The first of these, the BACE1-binding fragment in PDB, is from ACS-Omega.  The second, a new GtoImmuPdb S1P1 inhibitor entry, is from Pharmacology Research & Perspectives as the new Wiley/ASPET journal.

Two members associated with GtoPdb recently presented at the SAFER project kick-off meeting.  The aim is to provide mechanistic insights and pharmacological tools towards safer treatments for neurological diseases focusing initially on 5-HT2A and the training of PhD students.  As a proof of concept for capturing new relevant structures, we have now added a sub-nanomolar 5-HT2A inhibitor to the database.

New data in the Guide to IMMUNOPHARMACOLOGY (GtoImmuPdb)

Since the last release at least 32 targets and 66 ligands have been added to GtoImmuPdb. The 2018.1 release also coincides with the beta 3 release of the GtoImmuPdb portal – more details of which are available in a separate blog post. Other highlights include +20 ligands associated to immunological diseases, +1 target associated to disease, +57 targets associated to processes, and +8 targets associated to cell types.
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Posted in Database updates, Technical

Hot topic: The G Protein-Coupled Receptors deorphanization landscape.

Within the vast GPCR superfamily, orphans are described as receptors devoid of known endogenous ligands. They have been labeled as 7 transmembrane proteins by sequence homology and dispatched accordingly in the different GPCR subfamilies. They have attracted much attention given the recognized potential of GPCRs in terms of drug discovery. It is anticipated that discovering a new (and in the best case: previously unknown) ligand for an elusive receptor will open avenues in terms of innovative physiological concepts as well as unprecedented opportunities for drug discovery. However, after a couple of striking deorphanizations that confirmed their potential, the number of successful pairings between ligands and receptors has decreased.

The present paper by Laschet, Dupuis & Hanson [1] sheds some light on the current state of the field and the phenomenon of reduced discoveries in the orphan landscape. Although it is true that fewer deorphanizations have been reported recently compared to the 1990-2000 period, the authors propose that the rate has reached a “steady-state” stage. Nevertheless, with more than 100 remaining orphans, the daunting task of full deorphanization that lies ahead will require creative approaches both at the technical and conceptual level. Thus, following short historical reminders, the authors provide an extensive description of the current methods applied to deorphanization as well as emerging techniques that should help pharmacologists active in the orphan GPCR field in the near future. In addition, this review lists and discusses the deorphanizations that appeared in the literature since the last comprehensive state of the art issued by the IUPHAR (in 2013) [2] and put these pairings in their contexts, describing the probable outcomes in terms of new drug targets and previously unforeseen physiological loops.

Finally, during the collection of the recent literature about orphans, the authors noticed an important number of unconfirmed pairings and identified this as one of the major issues of the field and an important challenge for the future. Beside the deorphanized receptors that became silent after a single publication, presumably because of the failure of confirmation attempts by other teams, some ligands were openly questioned by recently published negative datasets. The paper proposes tentative explanations for inconsistencies in the literature and suggests recommendations such as critical controls that should be included when reporting a ligand for an orphan receptor.

Comments by Julien Hanson, University of Liege

  1. Laschet C, Dupuis N, Hanson J. (2018) The G Protein-Coupled Receptors deorphanization landscape. Biochem Pharmacol. pii: S0006-2952(18)30073-X. doi: 10.1016/j.bcp.2018.02.016. [Epub ahead of print] [PMID:29454621]
  2. Davenport AP, et al. (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G Protein-Coupled Receptor List: Recommendations for New Pairings with Cognate Ligands. Pharmacol Rev. 65: 967-86. [PMID:23686350]

Note, the GtoPdb latest pairings page tracks reports of novel pairings between orphan receptors and their ligands.

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Posted in Hot Topics

Hot topic: Pharmacogenomics of GPCR Drug Targets

A system of rigorous clinical trials and regulation exist to ensure that a new drug is safe and effective when reaching the market. However, natural human genetic variation(s) may cause individuals to respond differently to the same medication. A collaboration between the MRC Laboratory of Molecular Biology, Cambridge (UK), the Scripps Research Institute in Florida and the Department of Drug Design and Pharmacology, University of Copenhagen (home of the GPCRdb team) has now published a new detailed study on the effects of genetic variation in G protein-coupled receptors on responses to FDA-approved drugs [1].

The authors address the following main questions:

  • How variable are GPCR drug targets in the human population?
  • Are individuals with variant receptors likely to respond differently to drugs?
  • What is the estimated economic burden associated with variation in GPCR drug targets?

To address these questions, the authors have analysed datasets from multiple sources including genotype information from the 1,000 Genomes project, exome sequencing data from the exome aggregation consortium (ExAC), which contains aggregated information on genetic variants for ~60,000 ‘healthy’ individuals, structural information of receptors in complex with diverse ligands, data on functional effect of mutants and information on drug sales from the UK National Health Service.

The study reports that on average, an individual carries 68 missense variations in approximately one-third of the 108 GPCR drug targets. Many FDA approved drugs target a number of highly variable GPCRs. For example, several genetic variants for the mu-opioid receptor selected for experimental characterisation show an altered response for FDA-approved drugs, which could potentially lead to no or adverse reactions in the human population. Several variants occur within drug-binding sites and other functionally important positions, such as for the CCR5 drug-binding pocket of maraviroc, an antiretroviral drug for HIV treatment.

Based on an economic model, the authors estimated the potential economic burden due to ineffective prescribing of GPCR targeting drugs to be between 14 million and half-a-billion pounds annually in the UK alone.

This work might inspire many scientists to characterise human variants from multiple angles similar to the ENCODE project.

Key highlights:

  • GPCRs targeted by FDA-approved drugs show genetic variation in the human population
  • Genetic variation occurs in functional sites and may result in altered drug response
  • We present an online resource of GPCR genetic variants for pharmacogenomics research
  • Understanding variation in drug targets may help alleviate economic healthcare burden

(1) Hauser AS et al. (2017). Pharmacogenomics of GPCR Drug Targets. Cell, 172(1-2):41-54.e19. doi:10.1016/j.cell.2017.11.033. [PMID:29249361]

Comments by Alexander Hauser, University of Copenhagen and GPCRdb

While the above is a tour de force for GPCRs note also the genetic variation from 1K Genomes and/or ExAC can be accessed for every target protein in GtoPdb via the Ensembl gene ID we cross-reference.  

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Posted in Drug targets, Hot Topics

PubMed Commons and Altmetrics

This has been split from an updated older post on Citation profiles for our NAR and Concise Guide papers  and this section will be updated soon

PubMed Commons
In addition to keeping an eye on citations per se we also folow up on some of the newer ways of increasing the findability and connectivity of our work in the ever more complex bibleometrics/Social Media ecosystem.  These efforts are modest (compared to what can be done) since we have our heads down for the Day Job but some of them have become necessary  house-keeping . These include grant linking,  the addion of  ORCHIDs  for team members (both of these as  EPMC functionality) and making sure papers are entered into our very own Edinburgh Research Explorer (actually highly ranked in Google for title searches).

Two other aspects may be of  interest (they can’t be detailed here but background is in the links). The first of these is the use of PubMed Commons. that has several utilities for us, including being able to “daisy chain” forward citaion pointers (but you wont see them in EPMC yet).  For example, amoung the 73 PubMed  citations for our 2009 NAR paper, 7 are 2015 and 2 from 2016. Thus, some recent authors are still citing our oldest paper (we see this across the series in fact  but, to be fair, some of them could be giving us the courtesy of multiple NAR cites although I have not checked). We therefore came up with the strategy of adding discrete pointers in PubMed Commons. As it happened, the last one (pictured below) was added most recently, even thought it is first in the chain by abstract date.


So, if  the scholars in question happen to check PubMed (n.b. but not  BJP authors, since the most recent NAR reference would have been added by the Editors anyway) we have now have a set of  comments to point the four older papers forward to the fifth 2016 paper (and should we be fortunate enough to get accepted for a future NAR Database issue, we would then add a new comment to the chain).  Consequent to the posting above, an unexpectedly prominent  ping appeared  below, on the 2nd of Feb, highlighted in yellow.


In a nutshell, “Featured comments” just happend to automatically select ours (but it seems like an actual human edited it)  which consequently featured on the PubMed front page, no less, giving us 24 hours of micro-fame!  As icing on the cake, the concomitant dailly auto-tweet of the heuristic chart-toppers, shown below, reached 4394 followers of the PMCom account (and was re-tweeted by us of course)


Continuing on the metrics theme, in the panel below you can see Altmetrics scores for our same five NAR papers, plus the one Kudos entry.


These outlinks can be found under the right-most “External links” tab on any EPMC entry that has them. The Altmetrics Rosette and sub-scores give a general measure of interest asssociated with a paper (but dont forget this may not necessarily be completely positive)  broken down by category, as you can see for our 2016 NAR below;


Interesting aspects of Almetic scores include that they are faily immediate (i.e. accumulating within the first month or so)  and tend to move in the oposite direction to the slower accumulation of cites (i.e.they flatten off).  Here again, we alow ourselves a little warmth of feeling to see that the Altmetrics hueristics (while not incontravertable)  puts us close to the top-10% of comparable publications for both our GtoPdb NARs (i.e. we got the word out). The older papers, published during LBA (Life Before Altmetrics), clearly pick up lower scores. To conclude by putting it on the  record, we are most appreciative of colleagues and compatriots who explicitly draw positive attention to our work in both traditional and altenative ways.

Posted in Uncategorized

Hot topic: Trends in GPCR drug discovery: new agents, targets and indications

New avenues for GPCR drug discovery have emerged owing to recent advances in receptor pharmacology, technological breakthroughs in structural biology and innovations in biotechnology. A collaboration between the Department of Drug Design and Pharmacology, University of Copenhagen (home of the GPCRdb team) and the Uppsala University have published a detailed analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications [1].

By manually curating CenterWatch’s Drugs in Clinical Trials database and cross-referencing with public sources (such as Drugbank, Pharos and Open Targets), they were able to identify 475 approved drugs that target 108 unique GPCRs (~34% of all FDA-approved drugs) ( Additionally, there are approximately 321 agents that are currently investigated in clinical trials, of which ~20% target 66 potentially novel GPCR targets with no approved drug yet. Of these, 37 are peptide or protein-activated GPCRs.

Other relevant highlights:

  • Based on this data, the authors calculated GPCR-targeted agent success rates of 78%, 39% and 29% for phases I, II and III, respectively — slightly higher than the FDA’s average for all investigated agents.
  • There are early indications that the proportion of GPCR-targeted biologics such as monoclonal antibodies (mAbs) and other recombinant proteins is increasing in early stage clinical trials.
  • There is increasing focus on target selectivity rather than polypharmacology.
  • More allosteric modulators in early stage clinical trials.
  • CNS disorders remain highly represented among the indications of GPCR-targeted agents.
  • Diabetes is highly represented among the GPCR-targeted agents currently in clinical trials.
  • Opportunities are emerging for GPCR-targeted agents in oncology.
  • The GPCR structures are starting to impact drug discovery.

Currently, established GPCR drug targets are used by an average of 10.3 (median = 4) distinct approved agents. This indicates a near saturation of the current target space, and emphasizes the need to identify new druggable receptors in order to develop novel medications. The 224 (56%) non-olfactory GPCRs that are yet to be explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders.

Comments by Alexander Hauser and David Gloriam, University of Copenhagen and GPCRdb.

[1] Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. (2017) Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov. 16(12):829-842. doi: 10.1038/nrd.2017.178. [PMID:29075003]

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Posted in Hot Topics

Impact statements and content subsumation: BPS 2017 follow-up

We were pleased to catch up with many GtoPdb/GtoImmuPdb users, aficionados, friends and affiliates at the BPS Pharmacology 2017  in the QEII Center in London.  You can find our presentations and posters on Slideshare.  Associated with this presence we have an important request to ask of users and downloaders, plus a related request for the latter.  These are being made in the context of future funding considerations in general and a pending application to become an ELIXIR Europe Core Resource  in particular (we joined the UK ELIXIR Node Resources last year).

We need to collect and collate  “impact statements” (a.k.a. “use cases” or “translational stories”).  For this we would be most grateful to receive comments from users, regardless of whether new or experienced, academic or commercial.   We are pleased to have received many general compliments by different routes in recent years (including via our enquiries e-mail and Twitter) but we would like these new statements to give concrete and specific examples of the utility of our resource (detail is good but does not have to be long).   This can not only include answering scientific competency questions but also educational impact (e.g. as curricular inclusions for pharmacology teaching). We will contact some of you who we engaged with at BPS 2017 (where the level of positive response was gratifyingly high)  but please just e-mail us at our usual address: enquiries at

The second request is for those who either point to us as outlinks and/or subsume our content via downloads  or webservices. These may be either as part of integration efforts or simply bringing it inside their firewalls.  When we looked at in-links (i.e. resources pointing to us) last year were surprised to find well over 20 of these, about half of which we were unaware of.  From citations of our 2016 NAR Database Issue paper (PMID: 26464438) we have found several new ones but we think there may be more we have either not picked up and/or who have not contacted us.  Clearly, since having our content pointed to and/or subsumed is direct evidence of impact, we would be happy to have short testimonies to this effect, in particular why we were selected (n.b. commercial enterprises need not detail their internal why’s and wherefores but even general comments in this context are still useful).  If any parties could send both types of  examples (direct usage and subsumation) so much the better.

Note also that we welcome technical contact with all resources subsuming our content. This is not only to see if we can enhance the ease of this as a process but also to assist with making sure the latest releases are picked up. This is important since these have now reached six per year (a schedule we hope to maintain in 2018).  We are aware of some meta-portals whose internal update cycles exceed this so we want to avoid them missing out on our most recent data.

Clearly we need any comments you send us to be provenanced with personal professional identities and organisational affiliations. Notwithstanding, for those applications we are currently considering nothing will be publically surfaced.  Anyone who would like do us the favour of  presenting their use case but needs anonymity, is still welcome to contact us (n.b. enquiry mails are only seen by core team members)


Posted in Uncategorized

Database release 2017.6

The sixth and final IUPHAR/BPS Guide to PHARMACOLOGY release of 2017 has been published on 29th November. This release includes new content for the Guide to IMMUNOPHARMACOLOGY, which is currently still in beta phase. This release includes the following updates and new features:


Several new immunology-relevant proteins, across several target classes, have been added, along with ligands that interact with them.

target symbol TID target class GtoImmuPdb


Other protein y


Other protein y


Other protein y


Other protein y


Enzymes y


Catalytic Receptors y


Enzymes y

Further new ligands have also been added for existing targets.

The following existing targets have been reviewed and updated:


The GPCR overview text has been updated with information on pseudogenes and olfactory receptors.

Ion channels:

New website features

The ability to download the results of database searches has been added. Click on the “Download” button at the top of the search results page to download a CSV file listing some basic information on the targets, ligands and families in the results. The file includes GtoPdb identifiers, UniProt accessions, gene symbols and ids, and ligand chemical structure identifiers. We intend to develop this further, possibly with customisable download options, and we welcome feedback on this feature to inform future development.

Image showing the new Download button

New Download as CSV option for search results

The Guide to IMMUNOPHARMACOLOGY (GtoImmuPdb) has issued the beta v2.2 release (see more details in the November technical blog) which includes an extension to the target advanced search. This now enables searching across the main GtoImmuPdb data types (processes, cell type and disease). Built into this is inferred searching of Gene Ontology and Cell Ontology terms. By way of example, if a user searches on the term ‘cytokine’ this will match to any GO term containing that term. The search results will then bring back any targets annotated to that term or any of its children. The results will display the matched parent terms, plus a count of the number of child terms annotated to the target (see screenshot below).


The above screenshot shows the first results for a search on ‘cytokine’. The target TLR4 is returned as it is annotated to many GO terms, or their children, where the GO term contains the word ‘cytokine’. For example, TLR4 is annotated to 24 terms that are children of the term ‘regulation of cytokine production’.

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Posted in Database updates, Guide to Immunopharmacology, Technical

GtoPdb at Pharmacology 2017

The GtoPdb team will be at the British Pharmacological Society’s flagship meeting, Pharmacology 2017, in London, December 11-13th 2017.

We are pleased to have our own stand at this meeting and will be present during the refreshment breaks and poster sessions, where we look forward to speaking with database users and give live demos of the website. We will also be helping out at the Wiley stand in the Wiley Networking Lounge to publicise the Concise Guide to PHARMACOLOGY 2017/18, so look out for the events happening there and come and collect your free CGTP USB wristband!

In addition, GtoPdb team members will be presenting during the following slots in the main programme on Wednesday 13th Dec:

Oral Presentations

Abstract Number: OE004
Abstract Title: The IUPHAR/BPS Guide to PHARMACOLOGY in 2017: new features and updates
Date: Wednesday, December 13, 2017, 11:30 AM
Oral Session: Oral Communications: Education

Abstract Number: OB073
Abstract Title: Capturing new BIA 10-2474 molecular data in the IUPHAR/BPS Guide to PHARMACOLOGY
Date: Wednesday, December 13, 2017, 11:30 AM
Oral Session: Oral Communications: Mixed Tracks

Lunchtime Flash Poster Presentations

Flash Poster Number: FP35
Poster Number: PB128
Abstract Title: Iuphar guide to Immunopharmacology
Date: Wednesday 13 December 2017
Presentation Time: 1:15 PM – 1:45 PM

Flash Poster Number: FP33
Poster Number: PE005
Abstract Title: Navigating links between structures and papers: PubMed-to-PubChem connectivity from the Guide to PHARMACOLOGY and the British Journal of Pharmacology
Date: Wednesday 13 December 2017
Presentation Time: 1:15 PM – 1:45 PM

Poster Presentations

Abstract Number: PB128
Abstract Title: Iuphar guide to Immunopharmacology
Date: Wednesday, December 13, 2017, 2:45 PM
Poster Session: Poster Session: Integrated Systems Pharmacology

Abstract Number: PB135
Abstract Title: A systems pharmacology study of the cholesterol biosynthesis pathway
Date: Wednesday, December 13, 2017, 2:45 PM
Poster Session: Poster Session: Integrated Systems Pharmacology

Abstract Number: PE004
Abstract Title: The international Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR): Relevance to pharmacology today and challenges for the future
Date: Wednesday, December 13, 2017, 2:45 PM
Poster Session: Poster Session: Education and Skills

Abstract Number: PE005
Abstract Title: Navigating links between structures and papers: PubMed-to-PubChem connectivity from the Guide to PHARMACOLOGY and the British Journal of Pharmacology
Date: Wednesday, December 13, 2017, 2:45 PM
Poster Session: Poster Session: Education and Skills

Abstract Number: PE011
Abstract Title: The IUPHAR/BPS Guide to PHARMACOLOGY in 2017: new features and updates
Date: Wednesday, December 13, 2017, 2:45 PM
Poster Session: Poster Session: Education & Skills

We look forward to seeing you there!

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Posted in Concise Guide to Pharmacology, Events

GtoImmuPdb: technical update November 2017

This blog-post will discuss the major developments planned for the Guide to IMMUNOPHARMACOLOGY as we look ahead to our next beta-release (v3.0) in early 2018.

This month, the updated IUPHAR/BPS Guide to PHARMACOLOGY NAR Database Issue has been published online ( [PMID: 29149325]

The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY
Nucleic Acids Research, gkx1121,

As the title indicates, a major part of this update includes the expansion of the database and developments to produce the new Guide to IMMUNOPHARMACOLOGY. The paper discusses the unique targets and ligands that have been incorporated into GtoPdb as a consequences of the GtoImmuPdb Project. For example targets of relevance to immunity, inflammation and infection such as pattern recognition receptors and protein of the innate immune response. Database content statistics are presented with a specific breakdown for GtoImmuPdb content (Table 1).


Table 1. Taken from the NAR paper, table gives a breakdown of database content statistics, including GtoImmuPdb counts.

The paper goes into details on the development of the Guide to IMMUNOPHARMACOLOGY in terms of content & curation and how targets and ligands of immunological relevance are identified. There is detailed discussion on the process of incorporating the new process, cell type and disease data types for GtoImmuPdb as well as explanations of the novel portal and interfaces that have been developed to surface the GtoImmuPdb data.

The discussion and descriptions in the paper are related to the beta-release v2.0. Our next planned beta-release is due in early 2018. The developmental priorities for this release are;

  • Improving disease associations and display
  • Graphical browsing / navigation
  • Advanced search tool for immuno data types
  • Video help tutorials

For the disease data we are looking at developing new disease summary pages. These will not only serve to display target and ligand associations to disease of immunological relevance – but will also capture and display all disease-related data in the GtoPdb. This includes pathophysiology data and information on mutations. We are currently working-up some prototype pages, but expect to be able to have have some form of disease pages available in beta v3.0.

Using graphical illustrations of key biological pathways and cell types, as a way to summarise data can be very valuable. Enabling such graphics to be interactive and support navigation of a website may bring added value to the GtoImmuPdb resource. We are at the early stages of developing a cell types graphical-based navigation tool (Figure 2).


Figure 2. Graphical illustration of key immunological cell types. This forms the basis of providing a graphical-based navigation tool for GtoImmuPdb. Image copyrighted

Until now we haven’t developed the existing advanced search to cover GtoImmuPdb data types – this will be addressed in beta v3.0. We are also planning to provide video help tutorials to guide users in navigating the main GtoImmuPdb data types.

This project is supported by a 3-year grant awarded to Professor Jamie Davies at the University of Edinburgh by the Wellcome Trust (WT).

Posted in Guide to Immunopharmacology, Technical

Hot topic: Cryo-EM structures of Mucolipin TRP Channels in the Lysosome: Five Together at Once

The mucolipin subfamily of Transient Receptor Potential (TRP) channels, which consist of TRPML1, TRPML2, and TRPML3 (a.k.a. MCOLN1- 3), are Ca2+-permeable cation channels localized in intracellular endosomes and lysosomes. In response to cellular stimulation, TRPMLs mediate Ca2+ release from the lysosome lumen, triggering Ca2+-dependent lysosomal membrane trafficking events involved in a variety of basic cell biological processes, including lysosomal exocytosis, autophagy, and membrane repair [1]. In humans, loss-of-function mutations of TRPML1 cause type IV Mucolipidosis (ML-IV), a lysosome storage neurodegenerative disease (LSD). In mice, gain-of-function mutations of TRPML3 cause pigmentation and hearing defects [1]. Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), an endolysosome-specific phosphoinositide, may serve as an endogenous agonist of TRPMLs [2]. In addition, mucolipin-specific synthetic agonists (ML-SAs) have been identified and shown to regulate various TRPML-dependent lysosome functions by mimicking endogenous agonists [3]. Now, five independent studies, led by Youxing Jiang, Xiaochun Li, Soek-yong Lee, Maojun Yang, and Jian Yang, respectively, report a total of three TRPML1 and two TRPML3 Cryo-EM structures, all at atomic resolution, and in both closed and agonist-bound open conformations [4-8]. The general features of these channels are consistent across all five studies. Consistent with previous work [2], positively-charged amino acid residues in the cytoplasmic N–terminus are found to be responsible for channel activation by PI(3,5)P2 [7, 8]. In contrast, the synthetic agonist ML-SA1 binds to a separate site at an intriguing location. TRPML1 and TRPML3 are six-transmembrane (6TM) channel proteins with an overall topology similar to many other tetrameric cation channels, including KV channels. ML-SA1 binds to residues in the S5 and S6 [4, 6], domains that are known to form the “activation gate”. These five studies have provided a structural foundation for studying TRPML channel regulation, pharmacology, and lysosome chemical biology, which in turn may help develop new therapeutic strategies for a spectrum of lysosome-related diseases, including ML-IV, other LSDs, and common neurodegenerative diseases.

Comments by Haoxing Xu, NC-IUPHAR subcommittee Chair of the Transient Receptor Potential Channels and Professor, the University of Michigan


1. Xu, H. and D. Ren, Lysosomal physiology. Annu Rev Physiol, 2015. 77: p. 57-80. [PMID:25668017]

2. Dong, X.P., et al., PI(3,5)P(2) Controls Membrane Traffic by Direct Activation of Mucolipin Ca Release Channels in the Endolysosome. Nat Commun, 2010. 1(4). [PMID:20802798]

3. Shen, D., et al., Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release. Nat Commun, 2012. 3: p. 731. [PMID:22415822]

4. Zhou, X., et al., Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states. Nat Struct Mol Biol, 2017. [PMID:29106414]

5. Zhang, S., et al., Cryo-EM structures of the mammalian endo-lysosomal TRPML1 channel elucidate the combined regulation mechanism. Protein Cell, 2017. 8(11): p. 834-847. [PMID:28936784]

6. Schmiege, P., et al., Human TRPML1 channel structures in open and closed conformations. Nature, 2017. 550(7676): p. 366-370. [PMID:29019983]

7. Hirschi, M., et al., Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3. Nature, 2017. 550(7676): p. 411-414. [PMID:29019979]

8. Chen, Q., et al., Structure of mammalian endolysosomal TRPML1 channel in nanodiscs. Nature, 2017. 550(7676): p. 415-418. [PMID:29019981]

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Posted in Hot Topics

The Concise Guide to PHARMACOLOGY 2017/18


Concise Guide to Pharmacology Simplifies Drug Discovery Research

The Concise Guide to PHARMACOLOGY 2017/18 (CGTP), which is produced from a subset of the data contained in the IUPHAR/BPS Guide to PHARMACOLOGY database, is now available in the British Journal of Pharmacology. Published by Wiley on behalf of the British Pharmacological Society, the 440 page guide includes overviews of key properties for close to 1,700 human drug targets, identifies 3,500 ligands including more than 2,400 synthetic organic molecules and over 50 antibodies. Over 4,000 interactions between ligands and targets are quantified, allowing researchers to assess the potency of these interactions.

This open access knowledgebase of major drug targets is completely linked and divided into eight major areas of research focus:

  • G protein-coupled receptors
  • Ligand-gated ion channels
  • Voltage-gated ion channels
  • Other ion channels
  • Nuclear hormone receptors
  • Catalytic receptors
  • Enzymes
  • Transporters

It also includes an Overview chapter with additional information on other protein targets.

“As a pharmacologist, being able to access freely information on current human drug targets is vital to discovering new therapeutics,” said Steve Alexander, Associate Professor of Molecular Pharmacology, Faculty of Medicine & Health Sciences at the University of Nottingham and Lead Editor of the Concise Guide.

The Concise Guide provides an authoritative voice on nomenclature of these pharmacological targets through close links with NC-IUPHAR. It offers summary information on the best available pharmacological tools, alongside key references and suggestions for further reading.

“The Concise Guide to PHARMACOLOGY is the drug discovery researchers’ bible,” said Amrita Ahluwalia, Co-Director, The William Harvey Research Institute, Professor of Vascular Pharmacology at Barts & The London School of Medicine & Dentistry, and Editor-in-Chief of the British Journal of Pharmacology. “We are pleased to once again make the Concise Guide freely available to our colleagues around the globe at”

This edition of the Concise Guide was compiled with the help of over 150 collaborators representing industry and academia from 22 countries across four continents. The British Pharmacological Society and the Guide to PHARMACOLOGY database team would like to thank the CGTP editors, contributors, and colleagues at the Universities of Cambridge, Edinburgh, Nottingham in the UK, and Monash, Australia for their contributions to updating the Concise Guide to PHARMACOLOGY.

The Concise Guide is a handy starting point for teaching and researching on specific pharmacological targets. All the targets and ligands are also linked directly to the online database for further details. Please share this URL widely with your students and colleagues.


Alexander SPH, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Buneman OP, Cidlowski JA, Christopoulos A, Davenport AP, Fabbro D, Spedding M, Striessnig J, Davies JA; CGTP Collaborators. (2017) The Concise Guide to PHARMACOLOGY 2017/18. Br J Pharmacol. 174 (Suppl 1): S1-S446. [PMIDs: 29055037, 29055040, 29055033, 29055038, 29055036, 29055035, 29055034, 29055039, 29055032]

Publication URL:


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Posted in Concise Guide to Pharmacology, Publications

GtoPdb NAR database issue 2018: Journal to database connectivity and journal to GtoPdb links

The following blog post acts as supplementary data to the 2018 NAR Database Issue

Journal to Database connectivity

The citation provenance of all entity records and contextual comments selected by the curators and NC-IUPHAR members in GtoPdb is supported by four document types. These are journal papers with PubMed Identifiers (PMIDs, 30,894), journal papers without PMIDs (246), book references (72) and patent numbers (412). We also have 109 URL-only citations we have judged of good reputation and expected stability (some of which will get displaced when appropriate journal papers appear). The key axis of connectivity that we facilitate is PubChem-to-PubMed reciprocal linking. The importance of this overall has been described by the PubChem team in some detail, including the contribution of GtoPdb as one of the mapping sources [1].

The set of curated ligand references (for quantitative activity data at targets as well as selected ancillary references, such as completed clinical trial reports) form part of the SID records we submit to PubChem, which has a number of linking consequences. Note also that we uniquely specify the explicit location of the ligand structure within the reference. For example, ligand id: 8135 is named “compound 21 [PMID: 23312943]” and can thus be discriminated from no less than seven other “compound 21”s in the database by their specific PMID suffixes. Figure 1 illustrates the link between GtoPdb compounds and “Depositor Provided PubMed Citations” (DPPMC) both in the SID from us and merged in the CID from other submitters. Crucially, this relationship is reciprocal as we can see in the lower panel of Figure 1. This means that any user coming in to the NCBI Entrez system [2], either via PubMed or PubChem, can connect the paper to the structure or vice versa. In this example, we are the only source that has submitted a connection and the structure can be located in the paper (i.e. as compound 21). Conversely, popular compounds (e.g. approved drugs) may have PubMed connections in their CIDs from many submitters, but ours will include the quantitative binding data reference which may be before the drug was awarded an International Nonpropietary Name (INN).


Figure 1.  GtoPdb to PubChem to PubMed connectivity for ligand 8135.

Our overall PubMed statistics are shown in Table 1.

Table 1. GtoPdb PubMed statistics


All PMIDs curated into GtoPdb


Associated with target annotation


Associated with ligand annotation


Ligand SIDs (from 8978) that have PMID links


Total PMID links


Associated with ligand interactions or comments in PubChem


Associated with quantitative ligand interactions in PubChem



The majority of PMIDs (22,060) are associated with individual targets as well as commentaries on families, accumulated from curation and committee updates over 14 years. Internally we can attribute 9,673 PMIDs to ligand-specific references. From our 8978 SIDs, 82% have at least one DPPMC making a total of 9,086 PMID links. Of these, 6,011 refer to the quantitative interaction. We have analysed the journal breakdown for our ligands as shown in Figure 2 which reflects our empirical primary, secondary and tertiary reference classifications. For example, primary citations as first reports of binding data between ligands and targets are often selected from the Journal of Medicinal Chemistry, while we generally cite the British Journal of Pharmacology (BJP) in relation to in vivo rodent pharmacology, and occasionally the British Journal of Clinical Pharmacology (BJCP) for clinical trial reports. To discern if there was an immunopharmacological curation signal in our literature we compared Figure 2 with the PMIDs only from GtoImmuPdb. It was interesting to note that for the primary references we selected for quantitative ligand interactions, the overall pattern was similar. Notably, however, Journal of Immunology had moved up from a ranking of 17th in Figure 2 to 6th in the GtoImmuPdb references.


Figure 12.  Top-twenty journals from the 8,756 PMIDs cited in the interaction comments.

Journal-to-GtoPdb links

Our engagement with the BJP in the provision of live out-links has been described previously [3]. The major enhancement for this year is that Wiley have transitioned to in-line links in the text (at first mention), rather than the previous method of adding separate tables to the manuscripts. Taking the recent BJP papers from Volume 174, Issue 18 September 2017 as an example, the 12 papers therein have 134 out-links to GtoPdb. This year has also produced our first “circular” example where GtoPdb team members are co-authors on a Systems Pharmacology study, partly derived from the database for which we have added a set of links “back in” [4]. This year Wiley have also introduced the same GtoPdb out-links for the BJCP.

1. Kim, S., Thiessen, P.A., Cheng, T., Yu, B., Shoemaker, B.A., Wang, J., Bolton, E.E., Wang, Y. and Bryant, S.H. (2016) Literature information in PubChem: associations between PubChem records and scientific articles. J Cheminform, 8, 32. PMID: 27293485

2. Gibney, G. and Baxevanis, A.D. (2011) Searching NCBI databases using Entrez. Current protocols in bioinformatics, Chapter 1, Unit 1 3. PMID: 21975942

3. McGrath, J.C., Pawson, A.J., Sharman, J.L. and Alexander, S.P. (2015) BJP is linking its articles to the IUPHAR/BPS Guide to PHARMACOLOGY. Br J Pharmacol, 172, 2929-2932. PMID: 25965085

4. Benson, H., Watterson, S., Sharman, J., Mpamhanga, C., Parton, A., Southan, C., Harmar, A. and Ghazal, P. (2017) Is systems pharmacology ready to impact upon therapy development? A study on the cholesterol biosynthesis pathway. Br J Pharmacol. [Epub ahead of print] PMID: 28910500

Posted in Chemical curation

GtoPdb NAR database issue 2018: PubChem Content

The following blog post acts as supplementary data to the 2018 NAR Database Issue

GtoPdb PubChem Content

The GtoPdb PubChem integration strategy has been previously outlined (1). Since 2015 we have made nine PubChem submissions for new releases of our database. For 2017.5 (see release notes for version 2017.5) we now have 8978 Substance Identifiers (SIDs) (PubChem query “IUPHAR/BPS Guide to PHARMACOLOGY”[SourceName]). We submit within days of our public release but users should note that it can take PubChem a few days to complete the processing of a new submission and several weeks to complete the more computationally intensive relationship mappings (e.g. 3D neighbours).

It is valuable for users to be able to seamlessly navigate between bioactive chemistry content in these two resources. We therefore pay close attention to the correspondence between our internal ligand entries and the external PubChem records. For a range of technical reasons, we observe small discrepancies not only between inside and outside counts (e.g. for Compound Identifiers (CIDs)) but also the exact numbers associated with our content from derivative searches in PubChem (i.e. executed via several steps) which may depend on how the query is executed. We are in the process of investigating these minor but complex differences (including consulting with the PubChem team). In the interim we are being transparent in declaring differences between the internal counts in Table 1 and the external counts dealt with in this section.

The largest of our PubChem entries is the antisense polynucleotide mipomersen (ligand 7364) with a molecular weight (MW) of 7158. Our largest peptide entry (ligand 7387) is lixisenatide, with 44 amino acids and MW of 4858. We established that 2156 of our SIDs could not form CIDs (i.e. they had no representation in Simplified Molecular-Input Line-Entry System (SMILES) form) because they were proteins (i.e. mapped to an intact UniProtKB, large peptides or antibodies. Over the last two years we have been converting more curated peptides, and a limited number of therapeutic polynucleotides, without pre-existing CIDs, into SMILES. This enhances intra-PubChem connectivity for these increasingly important classes of ligands. To form a CID, these must be within the current upper limit of 1000 atoms, approximating to 70 residues for a peptide (Dr P Theissen, personal communication). For this reason, we have introduced the Sugar & Splice program (NextMove Software, Cambridge, UK) to facilitate our conversions of peptides to SMILES and Hierarchical Editing Language for Macromolecules (HELM) notation (15). While we have reached 273 peptide CID entries, we are continually coming up against the problem of authors insufficiently defining peptide modifications (e.g. by correct International Union of Pure and Applied Chemistry (IUPAC) terminology) for unequivocal translation to SMILES.

In Figure 1 we show an analysis of our content in PubChem.


Figure 1. Category breakdown at the SID (A) and CID(B) level for GtoPdb PubChem entries

For the SIDs (Figure 1A), we have introduced new annotation categories into our SID comment lines for users to be able to retrieve two important subsets. These are “approved drug true” (with “true” suffixed for technical reasons; most approvals have been passed by the FDA and/or European Medicines Agency (EMA)), and “immunopharmacology” for ligands specifically curated as part of GtoImmuPdb. For PubMed links, the connections have been made by us as a source. Note also that the intersect between approved drug and immunopharmacology is derived from our curation of publications suggesting the association but are not necessarily approved for immunological clinical indications. For the CIDs, the categories in Figure 1B are as described previously (1) except for the two new ones explained above. The CID counts for these are lower than their SID counts by 160 and 334 respectively because of the antibody component of both but also peptide content of the latter. The general pattern is approximately in proportion to our 10% ligand growth over two years, with the largest increase in the PubMed coverage (expanded on below).

One of the powerful consequences of our submitting to PubChem is to be able to compare between different sources, using filters for “slicing and dicing” (2). This is already introduced in Figure 1 by showing the ChEMBL overlap, but also, in terms of complementarity, to indicate we have 1595 CID structures ChEMBL does not.

The subject of the correctness of chemical structure representation within the pharmacological domain in general and GtoPdb is too extensive to be addressed here but we have an NC-IUPHAR committee specially to advise us on this important topic. Notwithstanding we use PubChem statistics as direct quality control for the structures we submit. This can be seen in Figure 1 where we have 326 structures no other source has submitted. The converse is reassuring in that just over 95% of our structures are supported by at least one other of the 545 sources in PubChem. While this is an argument for correctness there are caveats. The first of these is that two sources can independently submit an incorrect structure. The second is that all databases have an element of circularity where records can be re-cycled between sources. Inspection of our unique structures establishes that they include extractions from the literature that (for public sources) only we have made. An example is AZ13102909 (, where we derived the structure of a kinase inhibitor from an image in the paper ( Thus, we have introduced the additional triage of checking our unique 326 with the PubChem “same connectivity” operator to check relationships with other CIDs.

As a more detailed utility example, we generated CID comparisons to two other sources of similar size that also manually curate drugs and other pharmacologically active compounds. These are the well-established DrugBank (3) and the more recent DrugCentral (4). The former captures biochemical and pharmacological information about drugs, mechanisms and targets with recent expansion into absorption, distribution, metabolism, excretion and toxicity (ADMET). The emphasis of the latter is on active ingredients in all pharmaceutical formulations approved by the FDA and other regulatory agencies; in addition to structure and bioactivity the compounds are linked to drug label annotations and other regulatory information. The result is shown in Figure 2.


Figure 2. Intra-PubChem content comparison between GtoPdb, DugBank and DrugCentral. The union of all three is 14892. The PubChem latest submission dates for the sources were 23rd Aug 2017, 10th Feb 2016 and 2nd Sept 2017, respectively.

The overlaps and differences between these three sources quantify their complementarity. However, exact numbers can be confounded by minor differences in chemistry rules for their independent submissions (e.g. salts, parents or both) as well as different connectivity choices for the same compound skeleton (e.g. R versus S isomer). Notwithstanding, Figure 2 makes it clear the three sources have substantially different capture. The results also establish pairwise cross-corroboration (e.g. GtoPdb overlaps with 334 and 239 structures for which DrugBank and DrugCentral, respectively, diverge between each other). It should also be noted that GtoPdb was one of the sources used in the compilation of DrugCentral which would thus contribute to the 1276 overlap (4). The three-way intersect of 1037 should correspond to those approved drugs that can form CIDs. This is lower than expected (i.e. for the FDA would be predicted to be closer to 1500) but possible reasons for this have been discussed previously (5).


1. Southan, C., Sharman, J.L., Benson, H.E., Faccenda, E., Pawson, A.J., Alexander, S.P., Buneman, O.P., Davenport, A.P., McGrath, J.C., Peters, J.A. et al. (2016) The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucleic Acids Res, 44, D1054-1068. PMID: 26464438

2. Southan, C., Sitzmann, M. and Muresan, S. (2013) Comparing the chemical structure and protein content of ChEMBL, DrugBank, Human Metabolome Database and the Therapeutic Target Database. Molecular Informatics, 32 (11-12), 881-897. PMID: 24533037

3. Law, V., Knox, C., Djoumbou, Y., Jewison, T., Guo, A.C., Liu, Y., Maciejewski, A., Arndt, D., Wilson, M., Neveu, V. et al. (2014) DrugBank 4.0: shedding new light on drug metabolism. Nucleic Acids Res, 42, D1091-1097. PMID: 24203711

4. Ursu, O., Holmes, J., Knockel, J., Bologa, C.G., Yang, J.J., Mathias, S.L., Nelson, S.J. and Oprea, T.I. (2017) DrugCentral: online drug compendium. Nucleic Acids Res, 45, D932-D939. PMID: 27789690

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Posted in Chemical curation, Publications

Hot topic: A new research avenue investigating mitochondrial GPCR biology

As one of the first propositions for GPCRs being present in mitochondrial membranes, a recent report from Robert Friedlander and colleagues [1] follows on from previous work characterising synaptic and extrasynaptic mitochondria in human cortex (post-mortem samples) and their role in neuroprotection. This work, if reproduced, opens up new vistas, and has many implications for neurodegenerative diseases. Taken together, Suofu et al. show that melatonin is synthesised in mitochondria, that MT1 receptors are present in mitochondrial membranes, and that MT1 receptor stimulation reduces cytochrome c and caspase secretion caused by calcium overload. The authors propose that this is a mechanism for the neuroprotective effects of melatonin in hypoxic-ischaemic brain injury in neonatal and in models of Huntington’s disease, where there is mitochondrial impairment.

Comments by Michael Spedding, Secretary General, IUPHAR, and CEO, Spedding Research Solutions SARL, France

(1) Suofu Y et al. (2017). Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proc Natl Acad Sci U S A., pii: 201705768. doi: 10.1073/pnas.1705768114. [Epub ahead of print] [PMID:28874589]

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