GtoPdb: A resource for cell-based perturbogens
Poster for ELRIG, Möndal, 11/12 May 2017. This poster will also be presented at BioITWorld, Boston, May 23-25 A resource for the selection and interpretation of cell-based perturbogens: the IUPHAR/BPS Guide to PHARMACOLOGY Christopher Southan, Elena Faccenda, Joanna L. Sharman, Adam J. Pawson, Simon D. Harding, Jamie A Davies, Translational research requires the integration of the in vitro molecular mechanisms of action (mmoa) of small molecules, cell-based screening studies, animal models and eventual clinical trials. The International Union of Pharmacology (IUPHAR)/British Pharmacology Society (BPS) database, GtoPdb http://www.guidetopharmacology.org/ provides expert-annotated molecular interactions between endogenous receptor ligands, probes, lead compounds, clinical drugs and their protein targets. It thus provides a core set of quantitative pharmacological relationships that can be interrogated for many purposes, including those running cell-based screens, not only during result interpretation but also to identify key compounds for scoping and consolidation experiments. As described in [1] GtoPdb is populated by records extracted from pharmacology and medicinal chemistry journals, and released quarterly. Quality is ensured by curatorial stringency and our unique model of content selection based on recommendations from IUPHAR target class subcommittees of international experts collaborating with the in-house curators. The database now has over 14 000 binding values (mainly IC50, Ki or Kd) between 8000 ligands and 15000 human proteins (mainly primary but also secondary off-target interactions) representing a 7% druggable proteome. Our coverage is complementary to other sources. For example the 6565 structures we recently submitted to PubChem as CIDs, 5206 were not in DrugBank and 1535 not in ChEMBL. This includes recommended tool compounds with relatively defined mmoa (including 110 from the Structural Genomics Consortium Probe Portal). We also have 75% overlap with vendors for procurement and 80% with patent extractions that in many cases allow mapping to SAR data sets from first-filings (some of which we point to). In a cell screening context 1254 of our targets intersect with proteins in the Reactome pathway database. This is one way to select chemical peturbation points that could be detected by assay readouts. From Nov 2015 we have been funded by the Wellcome Trust to extend into immunopharmacology (within the existing database schema) that is now driving overall GtoPdb content expansion. Parties engaged in cell based assays using or could use compounds we have are encouraged to use GtoPdb, contact us for queries, possible analogue expansions and/or alert us to prospective new content. [1] Southan C et. al. (2016) Nucleic Acids Res. 44(D1):D1054-68, PMID: 26464438
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GtoPdb: A resource for cell-based perturbogens
- 1. Christopher Southan, Joanna L. Sharman, Adam J. Pawson, Simon D. Harding, Elena Faccenda, Jamie A. Davies Centre for Integrative Physiology, University of Edinburgh, EH8 9XD, UK. www.guidetopharmacology.org A resource for the selection and interpretation of cell-based perturbogens: the IUPHAR/BPS Guide to PHARMACOLOGY Unique content • Part of our value derives from relationship mapping stringencies, expert comments and unique content • This uniqueness arises from journal selectivity and frequent quarterly releases capturing new publications • We have ligand binding interactions for over 70 human proteins that are neither in DrugBank nor ChEMBL • Figure 3 (below) provides a breakdown of our PubChem content that indicated aspects of uniqueness • We submit all our ligands (as SIDs) but some are too large to be assigned compound identifiers (CIDs) • Over 1000 of these are receptor-binding peptides from the pharmacological literature • 320 of our structures are unique in PubChem (total 94m) • Compared to DrugBank we differ by over ½ their content • We have 1,535 CIDs not in ChEMBL Examples of GPCR database tables Conclusions • The ligand content of GtoPdb constitutes a “perturbation toolbox” for ~ 7% of the druggable proteome • Many of our ligands are not captured in other resources. • In a cell screening context, 1254 of our targets intersect with UniProt proteins in the Reactome pathway • We have most of the probes from the SGC probe portal, a wide range of inhibitors, agonists, allosteric binders, antagonists as well as radiolabeled ligands • Our database facilitates both direct browsing and download for integration into internal resources for chemogenomics and quantitative pharmacology • Those engaged in cell based assays using (or could use) compounds we have curated are encouraged to contact us for queries, possible analogue expansions from patents and alert us to prospective new papers for extraction • We have started a Wellcome funded project to extend data capture into the immunopharmacology domain Introduction • The Wellcome Trust funded International Union of Pharmacology (IUPHAR)/British Pharmacology Society (BPS) database (GtoPdb) provides annotated molecular interactions between endogenous receptor ligands, research compounds, leads, approved drugs, and their Swiss-Prot targets • Builds on the reputation of its predecessor IUPHAR-DB • The website can be easily interrogated by those running cell-based screens • Useful for result interpretation and to identify key compounds for scoping and consolidation experiments. Poster copy at www.slideshare.net/cdsouthan/gtopdb-a-resource-cellbased-perturbogens cdsouthan@hotmail.com Fig. 2. Breakdown of ligand by class in GtoPdb UK Node Resource for: Populating the database • As described in PMID 26464438, GtoPdb content is curated from pharmacology and medicinal chemistry journals, released quarterly, with PubChem updates • Quality is ensured by expert curation by a highly qualified team and our unique model of integrating recommendations from IUPHAR target class subcommittees of international experts • We have connected ~14,000 binding values (mainly IC50, Ki, Kd) between ~8,000 ligands (see Fig. 1) and ~1,500 human proteins (see Fig. 2 below) • We record reported secondary target interactions • We link to other chemistry and protein databases • We update approximately bi-monthly Fig. 1. Breakdown of human targets in GtoPdb Figure 3