The druggable genome concept, introduced by Hopkins and Groom in 2002 has steadily increased in its relevance to contempory drug discovery and now underpins the NIH Illuminating the Druggable Genome (IDG) Program. While the range of proteins with activity-modulating starting points supported by publications has expanded, getting hard target numbers is difficult. However, as an expert-curated database of approved, clinical or research level pharmacological targets mapped to defined ligands, the IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb) provides its own internal statistics on DG coverage. In addition, it actively submits cross-references to UniProtKB/Swiss-Prot. This is joined by the additional cross-refrences of target-to-chemistry resources of DrugBank, ChEMBL and BindingDB which, collectively provide data-supported DG numbers. This work compares overlaps and differences, functional coverage as well as cumulative target expansion between these four key databases. Comparative analysis of these four resources was perfomed via the UniProt query interface. Intersects and differentials were generated using the online Venny tool. Then Gene Ontology (GO) categories for selected protein identifier lists were displayed using the PANTHER resource. Further details, such as coverage by 3D structures, were analysed via the UniProt interface. In order of their mention above, the human Swiss-Prot counts were 1496, 2336, 3303 and 2462, respectively. This produced an outer limit total of 4223 (representing 21% of the canonical human proteome of 21,136) some of which are les well characterised (dark) potential targets. While the four-way consensus drops to 738 this core set thus has a well-corroborated likelihood of tractability for small molecule drug discovery and/or biologics. These metrics underline the differential coverage of these sources but encouragingly, the consensus had increased from 568 two years ago. Analysis by GO categories indicates the different data capture selectivity and curatorial stringencies between the sources. Results will also be presented on coverage of structures, pathways and diseases for consensus sets as determined by additional UniProt queries. Despite the caveat of some arguably loosely-mapped or false-positive entries, the four resources compared here provide accessible, complementary and cumulative coverage of the DG. This expands the number of potential starting points for new target validation and the development of new medicines.

Putting hard numbers on druggability: Comparing the IUPHAR/BPS Guide to Pharmacology with other chemistry-mapped sources in Swiss-Prot

256th National Meeting (2018)

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