Hopkins and Groom coined the term “druggable genome” in 2002 for the extrapolated total of ~ 10% of the human proteome likely to bind small molecules with lead-like chemical properties and sufficient binding affinity for activity modulation. Fast-forward to 2015 and the UniProtKB website now include four database cross-references in the new Chemistry section. These provide a more detailed picture, based largely on chemistry-to-protein mapping data curated from the literature. They are thus evidence-supported statistics rather than homology-based transitive estimates.   These included (Sept 2015) human protein links to 2927 target entries from ChEMBL, 2191 from BindingDB, 1563 from DrugBank and 1340 from the IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb).   Statistical comparisons between these will be presented here defining different levels evidence support and following their continued expansion. The union of all four sets, 3603, encompasses ~ 18% of the proteome. However, the proportion that would match the most stringently curated of these, GtoPdb for chemistry-to-protein mapping is lower and comparison indicate curation strategies and source selections for each database diverge considerably (PMID 24533037). This is manifest in the relatively high unique content of 1147 (31% of the union) for the sources.  However, they converge as a 4-way intersect for 490 proteins (13% of the union).  Concordance between at least two independent sources (i.e. the non-unique proportion) expands to 2456 or 12% of the proteome. This represents the most precise data-supported druggable proteome snapshot for each UniProtKB release. Orthogonal comparative analyses of these intersecting sets  will be presented, including by Gene Ontology functional categories,  target class content, secreted vs. non-secreted, and disease gene links.  The utility of this druggable proteome assessment is very high in pharmacology and drug discovery, especially in terms of being able to data mine leads as chemical starting points for target validation experiments.<br/>

Intersecting different databases to define the inner and outer limits of the data-supported druggable proteome

251st National Meeting (2016)

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