Chemogenomics approaches to G-protein coupled receptor lead finding.

Abstract

G-protein coupled receptors (GPCRs) are promising targets for the discovery of novel drugs. In order to identify novel chemical series, high-throughput screening (HTS) is often complemented by rational chemogenomics lead finding approaches. We have compiled a GPCR directed screening set by ligand-based virtual screening of our corporate compound database. This set of compounds is supplemented with novel libraries synthesized around proprietary scaffolds. These target-directed libraries are designed using the knowledge of privileged fragments and pharmacophores to address specific GPCR subfamilies (e.g., purinergic or chemokine-binding GPCRs). Experimental testing of the GPCR collection has provided novel chemical series for several GPCR targets including the adenosine A1, the P2Y12, and the chemokine CCR1 receptor. In addition, GPCR sequence motifs linked to the recognition of GPCR ligands (termed chemoprints) are identified using homology modeling, molecular docking, and experimental profiling. These chemoprints can support the design and synthesis of compound libraries tailor-made for a novel GPCR target.