Integrated Approaches for Genome-wide Interrogation of the Druggable Non-olfactory G Protein-coupled Receptor Superfamily

Abstract

G-protein-coupled receptors (GPCRs) are frequent and fruitful targets for drug discovery and development, as well as being off-targets for the side effects of a variety of medications. Much of the druggable non-olfactory human GPCR-ome remains under-interrogated, and we present here various approaches that we and others have used to shine light into these previously dark corners of the human genome.

Keywords: G-protein-coupled receptor (GPCR); chemical biology; cheminformatics; disease; druggable genome; functional genomics; molecular pharmacology; neurological disease.

FIGURE 1.

Many GPCRs are understudied. A, shown is a graph of PubMed publications for the non-olfactory GPCRs. For this graph, the time period studied was up to and including August 2013. For searching for publications referencing a particular GPCR, either the International Union of Basic and Clinical Pharmacology (IUPHAR)-approved name or the genome identifier was used, depending upon which resulted in the largest number of publications. B, many GPCRs have no identified chemical modulators. Shown is a graph of CheMBL compounds culled from GPCR SARfari (https://www.ebi.ac.uk/chembl/sarfari/gpcrsarfari) using version 3.00.

FIGURE 2.

The GPCR tree is (mainly) un-interrogated. Shown in tree-based format are the data from Fig. 1B plotted on the GPCR tree (courtesy of V. Katritch and R. C. Stevens—Scripps/USC).

FIGURE 3.

Understudied GPCRs continue to be understudied. Shown is a comparison of publications for individual GPCRs up to August 2013 (red) and for the entire year of 2014 (green; analysis performed March 2015). The vertical axis (number of publications) here is shown in log2 format to include both datasets on the same graph.