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Expansion of the druggable genome in the IUPHAR/BPS Guide to PHARMACOLOGY and other drug target resources: a key substrate for future medicines

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The International Union of Pharmacology
(IUPHAR)/British Pharmacology Society (BPS) database
(GtoPdb www.guidetopharmacology.org) curates
interactions between receptor ligands, research
compounds, approved drugs and their protein targets
(PMID 29149325). From 2012-15 we were funded by the
Wellcome Trust to expand the predecessor IUPHAR-DB of
receptors and channels to cover all data-supported
targets in the human proteome. Expansion continued
post-2015 with another
Wellcome Grant to extend into
Examples of GPCR database tables
extant and new immunopharmacology targets.

Published in: Science
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Expansion of the druggable genome in the IUPHAR/BPS Guide to PHARMACOLOGY and other drug target resources: a key substrate for future medicines

  1. 1. Christopher Southan, Joanna L. Sharman, Adam J. Pawson1, Simon D. Harding, Elena Faccenda and Jamie A. Davies. IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Discovery Brain Sciences, University of Edinburgh, EH8 9XD, UK. Expansion of the druggable genome in the IUPHAR/BPS Guide to PHARMACOLOGY and other drug target resources: a key substrate for future medicines Analysis of results From a current Swiss-Prot human proteome count of 20,341 we can calculate proportional coverage. The sum of all four sources represents 21% of the proteome, 2-way 4.7%, 3- way 5.4% and 4-way 3.4%. For the latter set of 740 proteins further analyses were performed. The Gene Ontology (GO) functional splits (Fig.3) show an even distribution between transport, binding, catalysis and receptors. The UniProt x-refs can give a detailed “slice and dice” for many characteristics. The selection presented (Fig. 4) includes the protease, kinase and GPCR splits, diseases in OMIM, EC number, transmembrane, PDB structures, Human Protein Atlas and pathway memberships (n.b. any such analysis can be performed on any subset from Fig.2). Examples of GPCR database tables Conclusions • For reasons than cannot be expanded here (see PMID 24533037) the four sources have individual selectivity for literature extraction, different release schedules and small proportions of likely false-positives. • Notwithstanding, they colectively provide complementary and acessible coverage of the DG. • Expansion is steady (e.g. the 4-way consensus has increased from 568 in 2016 to 740 in 2018) and may acellerate via new assay methodologies, probe compound development and a focus on less characterised targets. • Despite caviats, (e.g. medicinal chemistry tractability, druggability and target validation) these sources provide increasing numbers of potential therapeutic intervention points for the development of new medicines. Introduction The International Union of Pharmacology (IUPHAR)/British Pharmacology Society (BPS) database (GtoPdb www.guidetopharmacology.org) curates interactions between receptor ligands, research compounds, approved drugs and their protein targets (PMID 29149325). From 2012-15 we were funded by the Wellcome Trust to expand the predecessor IUPHAR-DB of receptors and channels to cover all data-supported targets in the human proteome. Expansion continued post-2015 with another Wellcome Grant to extend into extant and new immunopharmacology targets. cdsouthan@hotmail.com UK Node Resource for: UniProt cross-references (x-refs) Each of the databases (Fig.1) have curated chemistry- to-protein mappings for activity modulation and therefore probable tractability as potential targets. While data models and curatorial stringencies are different, the four selectable protein sets are compared in this work. Human Swiss-Prot lists were downloaded for each of the sources and a Venn diagram comparison made (Fig.2). Importantly, each source shows a proportion of unique content, indicating they have captured protein-to-chemistry interactions the other three have not. Note for GtoPdb the 1505 have quantitative ligand interactions (< from 1410 in 2016). Figure 1. The four sources of chemistry x-refs for human reviewed (Swiss-Prot) entries. Figure 2. Venn diagram comparing the four sources with protein totals shown after each database name. Figure 4. Attribute distributions in the 740 protein set. These were all derived from additional UniProt x-ref selections. Figure 3. Top-level GO classifications for the 740 protein set.

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