In Silico Drug Design for Purinergic GPCRs: Overview on Molecular Dynamics Applied to Adenosine and P2Y Receptors.

Molecular modeling has contributed to drug discovery for purinergic GPCRs, including adenosine receptors (ARs) and P2Y receptors (P2YRs). Experimental structures and homology modeling have proven to be useful in understanding and predicting structure activity relationships (SAR) of agonists and antagonists. This review provides an excursus on molecular dynamics (MD) simulations applied to ARs and P2YRs. The binding modes of newly synthesized AAR- and AAR-selective nucleoside derivatives, potentially of use against depression and inflammation, respectively, have been predicted to recapitulate their SAR and the species dependence of AAR affinity. P2YR and P2YR crystallographic structures, respectively, have provided a detailed understanding of the recognition of anti-inflammatory P2YR antagonists and a large group of allosteric and orthosteric antagonists of P2YR, an antithrombotic and neuroprotective target. MD of AAR (an anticancer and neuroprotective target), AAR, and P2YR has identified microswitches that are putatively involved in receptor activation. The approach pathways of different ligands toward AAR and P2YR binding sites have also been explored. AAR, AAR, and AAR were utilizes to study allosteric phenomena, but locating the binding site of structurally diverse allosteric modulators, such as an AAR enhancer LUF6000, is challenging. Ligand residence time, a predictor of in vivo efficacy, and the structural role of water were investigated through AAR MD simulations. Thus, new MD and other modeling algorithms have contributed to purinergic GPCR drug discovery.