Hot Topic: Unexplored therapeutic opportunities in the human genome

Contemporary drug discovery is dominated by two related  themes. The first of these is target validation upon which the sustainability of pharmaceutical R&D (in both the commercial and academic sectors) crucially depends.  The second is the size of the pool of human proteins that are/could become tractable to being progressed towards clinical efficacy as their final validation step (otherwise known as the druggable proteome).  This usefully detailed review, by a large team of authors, touches on both themes but with a focus on how the community might increase the target pool by data-driven knowledge expansion for hitherto less well characterised proteins [1].

As explained in the paper, this shortfall is being addressed by the NIH Illuminating the Druggable Genome (IDG) project since 2014 [2].  As essential reading for those engaging with the  intersects between pharmacology and drug discovery, just a few aspects can be picked out. One of these is their formalisation of a target development level (TDL) classification scheme of Tclin (clinical evidence), Tchem (chemical modulators), Tbio (biological data)  and Tdark related to the depth of investigation.  This “dark” category encompasses proteins with the least current knowledge (i.e. unvalidated potential targets) and a low number of (if  any) molecular probes.  Included in this are of course the orphan GPCRs that have been the subject of previous Hot Topics in their own right [3].

The authors not only point to many additional resources but also present a wealth of detailed statistics on many aspects of drug targets.  These included (Table 1) that eight olfactory receptors have Tbio level data.  Another nugget was the fact that phenomenological responses following radiation therapy is a bona fide biological functional characterisation approach that few of us are aware of. Last but not least, we were pleased to see GtoPdb [4] cited as one of the sources included in this impressive analysis.

For the record, our own curatorially-supported human druggable target list encompasses 1496 proteins with quantitative ligand interactions.  This can be found via the UniProt cross-reference. (n.b. this number will change slightly as the links from our own latest database release will update in the forthcoming UniProt release).

Comments by Chris Southan, IUPHAR/BPS Guide to PHARMACOLOGY, @cdsouthan
  1. Oprea TI et al. (2018). Unexplored therapeutic opportunities in the human genome. Nat Rev Drug Discov. doi: 10.1038/nrd.2018.14 [Epub ahead of print] [PMID:29472638]
  2. Illuminating the Druggable Genome (IDG) Program.
  3. Hot topic: The G Protein-Coupled Receptors deorphanization landscape.
  4. Southan C et al. (2016) The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands.  Nucleic Acids Res. 44(D1):D1054-68. doi: 10.1093/nar/gkv1037. [PMID:26464438]


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