Structure-Based Discovery of Novel Chemotypes for Adenosine A2A Receptor Antagonists

Abstract

The recent progress in crystallography of G-protein coupled receptors opens an unprecedented venue for structure-based GPCR drug discovery. To test efficiency of the structure-based approach, we performed molecular docking and virtual ligand screening (VLS) of more than 4 million commercially available “drug-like” and ‘‘lead-like’’ compounds against the A_2AAR 2.6 Å resolution crystal structure. Out of 56 high ranking compounds tested in A_2AAR binding assays, 23 showed affinities under 10 μM, 11 of those had sub-μM affinities and two compounds had affinities under 60 nM. The identified hits represent at least 9 different chemical scaffolds and are characterized by very high ligand efficiency (0.3−0.5 kcal/mol per heavy atom). Significant A_2AAR antagonist activities were confirmed for 10 out of 13 ligands tested in functional assays. High success rate, novelty, and diversity of the chemical scaffolds and strong ligand efficiency of the A_2AAR antagonists identified in this study suggest practical applicability of receptor-based VLS in GPCR drug discovery.