Computational Methods for GPCR Drug Discovery

Antonella Ciancetta, Kenneth A. Jacobson

Recent crystallographic structures of G protein-coupled receptors (GPCRs) have greatly advanced our understanding of the recognition of their diverse agonist and antagonist ligands. We illustrate here how this applies to A2A adenosine receptors (ARs) and to P2Y1 and P2Y12 receptors (P2YRs) for ADP. These X-ray structures have impacted the medicinal chemistry aimed at discovering new ligands for these two receptor families, including receptors that have not yet been crystallized but are closely related to the known structures. In this Chapter, we discuss recent structure-based drug design projects that led to the discovery of: (a) novel A3AR agonists based on a highly rigidified (N)-methanocarba scaffold for the treatment of chronic neuropathic pain and other conditions, (b) fluorescent probes of the ARs and P2Y14R, as chemical tools for structural probing of these GPCRs and for improving assay capabilities, and (c) new more drug-like antagonists of the inflammation-related P2Y14R. We also describe the computationally enabled molecular recognition of positive (for A3AR) and negative (P2Y1R) allosteric modulators that in some cases are shown to be consistent with structure-activity relationship (SAR) data. Thus, computational modeling has become an essential tool for the design of purine receptor ligands.