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 A₁AR- and A₃AR-selective nucleoside derivatives, potentially of use against depression and inflammation, respectively, have been predicted to recapitulate their SAR and the species dependence of A₃AR affinity. P2Y₁₂R and P2Y₁R crystallographic structures, respectively, have provided a detailed understanding of the recognition of anti-inflammatory P2Y₁₄R antagonists and a large group of allosteric and orthosteric antagonists of P2Y₁R, an antithrombotic and neuroprotective target. MD of A_2AAR (an anticancer and neuroprotective target), A₃AR, and P2Y₁R has identified microswitches that are putatively involved in receptor activation. The approach pathways of different ligands toward A_2AAR and P2Y₁R binding sites have also been explored. A₁AR, A_2AAR, and A₃AR were utilizes to study allosteric phenomena, but locating the binding site of structurally diverse allosteric modulators, such as an A₃AR enhancer LUF6000, is challenging. Ligand residence time, a predictor of in vivo efficacy, and the structural role of water were investigated through A_2AAR MD simulations. Thus, new MD and other modeling algorithms have contributed to purinergic GPCR drug discovery.