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.

commons-pointer

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.

pubmed_commons_comment_feb_2017

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)

pubmed_commons_tweet_feb_2017

Altmetrics
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.

altmetrics_nars

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;

altmetric

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.

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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) (http://www.gpcrdb.org/drugs/drugmapping). 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 guidetopharmacology.org

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:

Targets

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
VSIR

2956

Other protein y
BCL6

2957

Other protein y
FOXN1

2958

Other protein y
GPC3

2959

Other protein y
TRIM21

2967

Enzymes y
IL-1R8

2969

Catalytic Receptors y
EPHX2

2970

Enzymes y

Further new ligands have also been added for existing targets.

The following existing targets have been reviewed and updated:

GPCRs:

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).

cytokine_result

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 (https://academic.oup.com/nar/article/4628131). [PMID: 29149325]

The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY
Nucleic Acids Research, gkx1121, https://doi.org/10.1093/nar/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).

nar2018_table1

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).

pathophysiologyAutoImmunity_text800

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