Hot Topics: 3D structure of the full-length P2X7 receptor provides insight into factors controlling agonist potency and receptor desensitisation

P2X receptors are ligand-gated cation channels for which ATP is the endogenous orthosteric agonist. Seven P2X subunits have been identified and they form trimers to produce at least twelve different receptor subtypes. The tertiary structure of several subtypes have been reported, but they all lack clear information on the conformation of the N- and C-terminal cytoplasmic domains because of the truncated constructs used and the flexibility of these domains. Now, McCarthy et al., (1) report single-particle cryo-EM images of the full-length rat P2X7 receptor in both apo (closed pore) and ATP-bound (open pore) states, which suggest why the affinity of this receptor for ATP is low, indicate how cysteine residues in the C-terminal control desensitisation and reveal a surprising guanine nucleotide binding site in the C-terminal.

The potency of ATP at P2X7 is three orders of magnitude lower than at other P2X subtypes. Whilst these new structures show some differences between the orthosteric ATP binding pocket of P2X7 and P2X3 receptors, these are unlikely to explain the great difference in ATP potency. Notably, however, the entrance to the pocket is much narrower in P2X7 (<11A° orifice) than in P2X3 (17A° orifice) receptors. This and any protein flexibility that opens and closes the entrance would decrease the time ATP spends in the binding pocket, so decreasing its affinity.

A unique feature of P2X7 receptors is an 18-amino acid long cytoplasmic region at the end of TM2 (named the C-cys anchor by the authors) that is cysteine-rich and which links TM2 to the cytoplasmic cap, a structural domain formed by N- and C-terminal residues that determines the rate at which P2X receptors desensitise. The present report shows that the C-cys anchor contains at least four cysteine residues and one serine residue that are palmitoylated and that the aliphatic chains extend into the plasma membrane, anchoring the receptor to the membrane. The authors speculate that this could keep the cytoplasmic cap in place and so limit P2X7 desensitisation. Consistent with this, the receptor, which is normally non-desensitising in the presence of ATP, desensitised rapidly and fully when the C-cys anchor was deleted or the cysteine residues removed by mutation.

A further unique feature of P2X7 receptors compared with other subtypes is the long C-terminal (~200 residues), which the authors term the cytoplasmic ballast. The images show for the first time that each receptor has three globular, wedge-shaped cytoplasmic ballasts, each of which hangs beneath the TM domain of an adjacent subunit. Intriguingly, each cytoplasmic ballast contains a dinuclear zinc ion complex and a high-affinity guanosine nucleotide binding site, the functions of which are unclear.

The P2X7 receptor is of particular therapeutic interest because it is cytotoxic due to its ability to activate the NLRP3 inflammasome and release pro-inflammatory cytokines. This study substantially extends our knowledge and understanding of its pharmacological and biophysical properties and forms the basis of further potential experiments designed to fully characterise how it functions.

Comments by Dr. Charles Kennedy, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde

(1) McCarthy et al. (2019). Full-length P2X7 structures reveal how palmitoylation prevents channel desensitization. Cell. https://doi.org/10.1016/j.cell.2019.09.017. [ScienceDirect: View Article]

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Official Launch of the Guide to MALARIA PHARMACOLOGY

gtommv_bannerWe are delighted to announce the first full public release of the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY (abbreviated to GtoMPdb). This new web resource, designed specifically for malaria pharmacology, has been developed as a joint initiative between the International Union of Basic and Clinical Pharmacology (IUPHAR) and the Medicines for Malaria Venture (MMV). It has been constructed as an extension to the parent Guide to PHARMACOLOGY database (GtoPdb) and incorporates new pharmacological content, including molecular targets in the malaria parasite and interaction data for ligands with antimalarial activity. In addition, a dedicated portal has been developed, in consultation with key opinion leaders in malaria research, to provide quick and focused access to these new data.

Screen Shot 2019-09-26 at 15.32.20The GtoMPdb portal homepage

A more detailed introduction to the project and a chronicle of technical developments can be found in our previous blog posts.

This initiative has enriched the GtoPdb and it is hoped will foster innovation by providing, in a single expert-curated database, results from antimalarial drug discovery programmes and the scientific literature. Following the lastest database release (2019.4), the Antimalarial targets family and the Antimalarial ligands family were updated and now contain a total of 30 P. falciparum (3D7) targets and 72 ligands annotated with antimalarial activity. The GtoMPdb has maintenance funding, ensuring new data curation will continue until June 2020.

We would like to take this opportunity to thank everyone involved in the project and for the helpful feedback we received during beta-testing of the portal. If you have any further feedback or queries about the resource please contact enquiries@guidetopharmacology.org

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

 

 

 

 

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Posted in Guide to Malaria Pharmacology

Database Release 2019.4

We are very pleased to announce our a new release of the IUPHAR/BPS Guide to Pharmacology. This version (2019.4) is the fourth this year and includes the first full-release of the IUPHAR/MMV Guide to Malaria Pharmacology.

Content Updates

GtoPdb now contains over 9,800 ligands, with around 7,450 having quantitative interaction data to biological targets. 1,442 of the ligands are approved drugs. The database contains over 1,700 human targets with curated interactions, with just over 1,500 of these having quantitative data. Full stats can be found on our About Page.

Here’s a brief summary of some of main curatorial updates:

  • The Lysyl oxidases family has been added to allow the GtoPdb to capture advance in medicinal chemistry and development of lysyl oxidase inhibitors. Lysyl oxidases are extracellular enzymes that are vital for cross-linking fibrillar elastin and collagens and for extracellular matrix stabilisation. LOX and LOXL2 are implicated in fibrosis, tumourigenesis, and metastasis, and are subsequently molecular targets for cancer drug discovery.
  • We have cross-referenced GtoPdb ligands against the World Health Organization (WHO) Model List of Essential Medicines, and now include this subset as a specific ligand category on our ligand list page. This classification is also displayed on ligand summary pages. Currently, 193 ligands in GtoPdb are on the WHO list.

Guide to Malaria Pharmacology (GtoMPdb)

We are delighted to officially launch the first full public release of the IUPHAR/MMV Guide to Malaria Pharmacology. GtoMPdb has been constructed in partnership with the Medicines for Malaria Venture (MMV), an organization dedicated to identifying, developing and delivering new antimalarial therapies that are both effective and affordable. This is in response to the global challenge of over 200 million cases of malaria and 400 000 deaths worldwide, with the majority in the WHO Africa Region.  It provides new pharmacological content, including molecular targets in the malaria parasite and interaction data for ligands with antimalarial activity.  We have pioneered curation of data from assays screening compounds against the whole organism, used routinely in antimalarial drug discovery.

A dedicated portal has been developed to provide quick and focused access to these new data and we have added direct links on the main GtoPbd home page.

home6

GtoPdb home page with new menu bar links to GtoMPdb.

In this database release these are the recent advancements made in the GtoMPdb.

  • The Antimalarial targets family and the Antimalarial ligands family have been updated, giving a total of 30 P. falciparum (3D7) targets and 72 ligands tagged as antimalarial in the database.
  • We have fixed the display of interactions to avoid duplicate rows – now data for a single target, ligand and species will appear together.

You can read more about the launch at this blog post.

Other Updates

Immunopharmacology content statistics

On the immunopharmaoclogy help page we have added a dynamic list of database content stats.

External links in Europe PMC

The GtoPdb has recently been included in the External Links service at Europe PMC (EPMC)  (https://europepmc.org/LabsLink). On EPMC pages, links to target and ligand entries have been added to the papers curated by GtoPdb that include a quantitative description of the ligand-target interaction. It is possible to retrieve all these references at EMPC by running an “Advanced Search” and selecting “IUPHAR/BPS Guide to Pharmacology” from the “External Links” drop-down list (LABS_PUBS:”1969″) as the cross-reference query. This currently gives 1,729 results, which can be further combined as Boolean-type queries against all other types of EPMC indexing including Bibliographic Fields, Filters, Data Links, External Links and Annotations.

empc

External Links for PMC:6452685 – showing links back to GtoPdb targets and ligands.

Bioschemas

We are also working with Bioschemas (http://bioschemas.org/) (35) to add schema.org semantic mark-up to GtoPdb, which will make it simpler for search engines to index the website. Our current focus is on implementing mark-up on all ligand summary pages, including properties from the Bioschemas MolcularEntity profile (https://bioschemas.org/specifications/drafts/MolecularEntity). A first version of the ligand mark-up has been added, but it remains a work in progress as we seek to refine it.

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

Hot Topics: GPR139 as a potential target for increasing opioid safety

The cross-talk between different G protein-coupled receptor signal-transduction pathways is an intriguing concept with important physiological implications [1]. A recent study by Wang et al. [2] has discovered that the actions of opioid drugs on the μ-opioid receptor (MOR) are negatively regulated by an interaction with the undercharacterized GPR139 receptor [3]. These findings implicate GPR139 as a potential target for increasing opioid safety.

The authors first identified opioid modulators using a transgenic C. elegans platform that were engineered to express the human MOR (tgMOR). Using a rapid behavioral readout to screen ∼2,500 mutagenized tgMOR worms, the authors identified ∼900 mutants with abnormal sensitivity to the opioid agonists morphine and fentanyl. In this paradigm, hypersensitive mutants recovered more rapidly from opioid-induced paralysis compared to the tgMOR animals. The authors focused on two mutants, one with homology to the L-type Ca2+ channel that is known to potentiate the nociceptive properties of opioids and the other frpr-13 that shares a phylogeny with the mammalian receptor GPR139. Furthermore, the opioid hypersensitivity in transgenic worms was reversed by the overexpression human GPR139, suggestive of a functional interaction between the receptors.

The authors then performed a variety of supporting in vitro functional assays in HEK293T cells that indicated GPR139 overexpression could attenuate or abolish MOR signaling and cell-surface expression. They also demonstrated that GPR139 and MOR were associating when co-expressed in this model system, although the relevance of this interaction in a native system awaits further investigation. Nevertheless, GPR139 and MOR were co-expressed in mouse neurons in brain regions implicated in opioid reward, analgesia and withdrawal. Moreover, a series of electrophysiological experiments using knockout mice indicated that GPR139 may offset the opioid-mediated inhibitory effects on neuronal firing.

On the basis of these compelling data, the authors then investigated the behavioural correlate of the GPR139 and MOR interaction. Although GPR139 knockout mice were ostensibly healthy, they exhibited consistently increased acute responses to morphine, including in a conditioned place preference paradigm as a measure of opioid reward, as well as in thermal and mechanical pain models. Equally, the GPR139 knockout mice exhibited fewer behavioural signs of withdrawal following the cessation of chronic opioid exposure. In a final set of experiments, the administration of a GPR139 surrogate agonist JNJ-63533054 led to a dose-dependent reduction in morphine analgesia in both pain paradigms in wild-type mice [4]. JNJ-63533054 also markedly suppressed the self-administration of morphine these mice. Strikingly, these effects were absent in the Gpr139−/− mice, strongly implicating GPR139 as a negative regulator of opioid response in vivo.

Taken together, these findings suggest that GPR139 could be pharmacologically targeted in a strategy to increase the safety and efficacy of opioid treatment, which is currently an area of widespread public interest. Intriguingly, this study builds on the previous identification of α-Melanocyte Stimulating Hormone (αMSH) as a potential endogenous ligand for GPR139 [5]. Given that αMSH is derived from the same precursor as another MOR ligand (β-endorphin), these findings may further indicate an important physiological interaction between these receptors. It will be of great interest to dissect the pharmacology of GPR139 activation, particularly in terms of potential therapeutic advantages over the direct inhibition of MOR.

Comments by Simon R. Foster, Postdoctoral Research Fellow at Monash University and David E. Gloriam (@David_Gloriam), Professor at University of Copenhagen and Head of GPCRdb.

(1) Selbie, L. A. & Hill, S. J. G protein-coupled-receptor cross-talk: the fine-tuning of multiple receptor-signalling pathways. Trends in pharmacological sciences 19, 87-93, (1998). [PMID: 9584624]
(2) Wang, D. et al. Genetic behavioral screen identifies an orphan anti-opioid system. Science (New York, N.Y.), eaau2078, (2019). [PMID: 31416932]
(3) Vedel, L., Nohr, A. C., Gloriam, D. E. & Brauner-Osborne, H. Pharmacology and function of the orphan GPR139 G protein-coupled receptor. Basic & clinical pharmacology & toxicology, (2019). [PMID: 31132229]
(4) Liu, C. et al. GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids l-Tryptophan and l-Phenylalanine. Molecular pharmacology 88, 911-925, (2015). [PMID: 26349500]
(5) Nohr, A. C. et al. The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), alpha-, and beta-melanocyte stimulating hormone (alpha-MSH, and beta-MSH), and the conserved core motif HFRW. Neurochem Int 102, 105-113, (2017). [PMID: 27916541]

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Hot Topics: Resting-State Structure and Gating Mechanism of a Voltage-Gated Sodium Channel

In this report the Catterall laboratory succeeded in solving the high resolution structure of a voltage-gated Na+-channel (Nav) in its resting state (1). Why is this difficult and why is this important? It is difficult because Navs exist in the resting state only at very negative voltages but not at a zero membrane potential required for structural analysis by X-ray crystallography or cryo-EM. Accordingly, all high resolution structures of Navs, whether pro- or eukaryotic, have so far reported channels with the voltage-sensing domains in the depolarized state, i.e. the positively charges S4 helices of the voltage sensors moved “up” towards the extracellular side. Therefore it is not known how the activation gate of the ion pore (formed by the four S6 helices) is kept closed by the voltage sensor in its resting position, i.e. with the S4-helices “down”. Some predictions about how this might work was inferred from structural work on related voltage-gated ion channels (e.g in a TPC1 channel, 2) or from a study in which a chimeric Nav construct was trapped in a closed (“deactivated”) state by a toxin (3). The elegant work presented here by Wideschaisri and colleagues (1) directly addressed this important question by generating suitable mutants of the bacterial Nav, NavAb (4). One mutant (KAV mutation) was engineered to shift its activation threshold to much higher voltages thus holding the channel in the resting state also at 0 mV for structural studies. Moreover, they introduced disulfide crosslinks locking the voltage-sensor in the desired resting (S4 “down”) or activated (S4 “up”) state. The stabilization of these states in these mutants were verified in functional studies to ensure that the structural data have clear functional correlates. Analysis of the X-ray structures (and cryo-EM structure for the KAV mutant) provided important novel insight into the structural rearrangements associated with the transition from the activated/open to the resting/closed state. This includes changes of the helical structure of S4 associated with its striking inward movement of about 11.5 A compatible with a “sliding helix” model. Rearrangements of the four S4-S5 linkers were found to tighten the “collar” around the S5 and S6 segments thus keeping the pore closed.
All this was possible because they used the bacterial NavAb, for their experiments. This comes with the advantage that this channel exists as a tetramer of identical subunits and therefore the mutations are present in all four voltage-sensors. This also facilitated disulfide cross-linking, because these channels lack endogenous cysteines. The disadvantage of NavAb is that it does not reflect the more complex structure of eukaryotic Nav and voltage-gated Ca2+ channels (Cavs) in which all four voltage-sensing- and pore forming elements are different and are tethered together in a single molecule. Nevertheless, there is no doubt that this “sliding helix” model of electromechanical coupling will also apply to eukarytic Navs and Cavs. Understanding all the conformational rearrangements occurring between resting and activated channel states will provide new opportunities for the discovery of state-dependent and subtype-selective Nav- and Cav- channel blocking drugs.

Comments by Jörg Striessnig, University of Innsbruck

(1) Wisedchaisri, G., Tonggu, L., McCord, E., Gamal El-Din, T.M., Wang, L., Zheng, N., Catterall, W.A., 2019. Resting-State Structure and Gating Mechanism of a Voltage-Gated Sodium Channel. Cell 178, 993-1003. doi: 10.1016/j.cell.2019.06.031. [PMID: 31353218]
(2) Kintzer, A.F., Green, E.M., Dominik, P.K., Bridges, M., Armache, J.-P., Deneka, D., Kim, S.S., Hubbell, W., Kossiakoff, A.A., Cheng, Y., Stroud, R.M., 2018. Structural basis for activation of voltage sensor domains in an ion channel TPC1. Proc. Natl. Acad. Sci. U.S.A. 115, E9095–E9104. doi: 10.1073/pnas.1805651115. [PMID: 30190435]
(3) Xu, H., Li, T., Rohou, A., Arthur, C.P., Tzakoniati, F., Wong, E., Estevez, A., Kugel, C., Franke, Y., Chen, J., Ciferri, C., Hackos, D.H., Koth, C.M., Payandeh, J., 2019. Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin. Cell 176, 702-715.e14. doi: 10.1016/j.cell.2018.12.018. [PMID: 30661758]
(4) Payandeh, J., Scheuer, T., Zheng, N., Catterall, W.A., 2011. The crystal structure of a voltage-gated sodium channel. Nature 475, 353–358. doi: 10.1038/nature10238. [PMID: 21743477]

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Hot Topics: The atlas of aminergic GPCR mutagenesis

G protein-coupled receptors (GPCRs) are an important family of signal-transducing membrane proteins capable of binding various types of ligands from the extracellular space and activating various signalling pathways inside the cell, rendering them one of the largest protein target families in pharmaceutical research [1]. Receptors of the aminergic GPCRs family are particularly rewarding drug targets as they are implicated in various disease areas, and structure-based drug design has enabled the understanding of ligand binding and function, and the development of more than 500 approved drugs targeting these receptors. Advances in structural biology allowed the determination of more than 300 crystal structures of more than 60 GPCR subtypes to date [2], however, these still represent only a small fraction of known receptor-ligand associations [3].

Site-directed mutagenesis (SDM) is a versatile and frequently employed tool in pharmacological investigations used to infer structural features of protein-ligand interactions [4]. Mutation studies complement structural information provided by crystal structures by defining the roles and relative importance of residues involved in binding, functional activity, and selectivity for ligand chemotypes which have not yet been co-crystallized with their receptors. Community-wide GPCR structure modelling challenges have shown that the best models could be constructed by careful incorporation of mutation and SAR data relating to ligand binding [5]. However, an integrated analysis of receptor and ligand structures and SAR, mutation data, and binding mode prediction has been so far lacking.

The study of Vass et al. can be regarded as a meta-analysis of the site-directed mutagenesis literature for aminergic G protein-coupled receptors [6]. Through an exhaustive database and literature search, the researchers from VU University Amsterdam, Polish Academy of Sciences, University of Copenhagen and Sosei Heptares have collected 6692 mutational data points for 34 aminergic GPCR subtypes of 8 species from 302 publications, covering the chemical space of 540 unique ligands from mutagenesis experiments. This large body of mutation data was also annotated with the structure-based GPCR residue numbering enabling a comparison of mutation effects across different GPCR subtypes and sub-families, and mapped onto the residue positions in the available aminergic crystal structures. Mutation effects were binned into four categories: increased effect, no effect, decreased, and abolished effect, and the data is presented in large overview tables for the five aminergic sub-families. For ligands which had not yet been co-crystallized with their respective receptors, the authors provide predicted binding modes using a combined docking and interaction fingerprint approach to rationalize the mutation effects in light of the ligand SAR.

For each receptor sub-family, a discussion of the known structural receptor-ligand interactions, the ligand chemical space, the structural determinants of receptor-ligand interactions from mutation studies in the amine, major, minor pockets, and the extracellular vestibule, and the possibility of mutation effect extrapolation is provided. The authors also discuss mutation effects of the same ligands across different receptors providing insights into the receptor specific determinants of ligand binding. Finally, an overview is provided of some applications, and the possibilities and limitations of using mutation data to guide the design of novel aminergic receptor ligands.

The authors have deposited the data on Zenodo and in the GPCRdb, and a KNIME workflow was also provided using the 3D-e-Chem KNIME nodes to ease further analysis of the data by the readers [7].

Comments by Chris De Graaf (@Chris_de_Graaf), Director Computation Chemistry, Sosei Heptares.

(1) Santos et al. (2017). A comprehensive map of molecular drug targets. Nat Rev Drug Discov. doi: 10.1038/nrd.2016.230. [PMIDs: 27910877]

(2) Munk et al. (2019). An online resource for GPCR structure determination and analysis. Nat Methods. doi: 10.1038/s41592-018-0302-x. [PMIDs: 30664776]

(3) Vass et al. (2018). Chemical Diversity in the G Protein-Coupled Receptor Superfamily. Trends Pharmacol Sci. doi: 10.1016/j.tips.2018.02.004. [PMIDs: 29576399]

(4) a) Munk et al. (2016). Integrating structural and mutagenesis data to elucidate GPCR ligand binding. Curr Opin Pharmacol. doi: 10.1016/j.coph.2016.07.003. [PMIDs: 27475047] b) Arimont et al. (2017) Structural Analysis of Chemokine Receptor–Ligand Interactions. J Med Chem doi: 10.1021/acs.jmedchem.6b0130. [PMIDs: 28165741]. c) Jespers et al. (2018). Structural Mapping of Adenosine Receptor Mutations: Ligand Binding and Signaling Mechanisms. Trends Pharmacol Sci. doi: 10.1016/j.tips.2017.11.001. [PMIDs: 29203139]

(5) a) Kufareva et al. (2011) Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment. Structure. doi: 10.1016/j.str.2011.05.012. [PMIDs: 21827947]; b) Kufareva et al. (2014). Advances in GPCR modeling evaluated by the GPCR Dock 2013 assessment: meeting new challenges. Structure. doi: 10.1016/j.str.2014.06.012. [PMIDs: 25066135]

(6) Vass et al. (2019). Aminergic GPCR-Ligand Interactions: A Chemical and Structural Map of Receptor Mutation Data. J Med Chem. doi: 10.1021/acs.jmedchem.8b00836. [PMIDs: 30351004]

(7) (a) https://3d-e-chem.github.io/; (b) http://doi.org/10.5281/zenodo.58104

Posted in Hot Topics

Database Release 2019.3

We have now made the third IUPHAR/BPS Guide to Pharmacology database release of 2019 (2019.3). It includes updates focussed on preparation for the next edition of The Concise Guide to PHARMACOLOGY (2019/20), due out later this year.

Content Updates

GtoPdb now contains over 9,600 ligands, with around 7,300 have quantitative interaction data to biological targets. 1,426 of the ligands are approved drugs. The database contains over 1,700 human targets, with just over 1,500 of these having quantitative interaction data. Full stats can be found on our About Page.

Here’s a brief summary of some of main curatorial updates:

  • The cereblon protein has been added as a new target. For simplicity it is included in the Enzymes section of the Guide, as it is an important component of the E3 ubiquitin ligase complex, although it has no intrinsic catalytic activity. Cereblon is included in the Guide as its binding by thalidomide class drugs has been identified as the molecular mechanism that underlies the teratogenicity of this drug class. We have included quantitative data for interactions between cereblon and the three approved thalidomide type drugs (thalidomide, lenalidomide and pomalidomide), as well as an Immunopharmacology comment and information about clinical variants in disease.
  • The neuromedin U receptor family has an updated detailed introduction.
  • Several ‘new to the GtoPdb’ corticotropin releasing factor-1 (CRF-1) receptor antagonists (ligand IDs 10375-10379), their receptor interaction data and histories as clinical candidates have been added, including verucerfont and pexacerfont.
  • Nudix hydrolase 7, an enzyme that is involved in peroxisomal CoA/acyl-CoA homeostasis, and the first reported covalent NUDT7 inhibitor (NUDT7-COV-1) were added.
  • The Guanyly Cyclases were reorganised. A new family, Receptor guanylyl cyclases (RGC) family, was created and the existing RGC family was renamed Transmembrane guanylyl cyclases (and added as a sub-family of the new family). Nitric oxide (NO)-sensitive (soluble) guanylyl cyclase was also moved within this new family. The NPR-C (natriuetic peptide receptor 3) target was moved to the Transmembrane guanylyl cyclases family and the Natriuretic peptide receptor family removed entirely from the Catalytic receptor class.
  • We generated HELM annotation and SMILES for the small cyclic peptide apelin receptor agonist MM07 and these were submitted to PubChem. See reference PMID:25712721

Guide to Malaria Pharmacology (GtoMPdb)

Earlier this year we issue a blog post introducing the Guide to Malaria Pharmacology. This gives a good background to the project and illustrates how we plan to handle curation of this data and how we are developing the new portal that accesses the data.

Thursday 25th of April was World Malaria Day 2019 and to raise awareness we issued a blog post and a news release, in conjunction with Edinburgh Infectious Diseases and the School of Biological Sciences. These highlighted the release of the GtoMPdb and also provided an account of the long association malaria research has had with Edinburgh.

In this database release these are the recent advancements made in the GtoMPdb.

tcp_list

Screenshot showing antimalarial ligands with Target Candidate Profiles (TCPs)

Other Updates

ChEMBL Target Links

Following on from the update to these links in the last release, we’ve finished updating the various place across the GtoPdb site the link out to ChEMBL.

Site search

Our site-wide search now works using ‘*’ as a wildcard indicator at the end of a search string. This helps make our search behaviour more consistent with other web-resources.

Other minor updates

Posted in Database updates, Guide to Malaria Pharmacology, Hot Topics