Discovery of novel and potent P2YR antagonists structure-based virtual screening for the treatment of acute gouty arthritis.

P2Y nucleotide receptor is a Gi protein-coupled receptor, which is widely involved in physiological and pathologic events. Although several P2YR antagonists have been developed thus far, few have successfully been developed into a therapeutic drug. In this study, on the basis of two P2YR homology models, Glide docking-based virtual screening (VS) strategy was employed for finding potent P2YR antagonists with novel chemical architectures. A total of 19 structurally diverse compounds identified by VS and drug-like properties testing were set to experimental testing. 10 of them showed good inhibitory effects against the P2YR (IC < 50 nM), including four compounds (compounds , , and ) with IC value below 10 nM. The best VS hit, compound exhibited the best antagonistic activity, with IC value of 2.46 nM. More importantly, compound restrained monosodium uric acid (MSU)-induced pyroptosis of THP-1 cells through blocking the activation of Nod-like receptor 3 (NLRP3) inflammasome, which was attributed to its inhibitory effects on P2YR-cAMP pathways. The key favorable residues uncovered using MM/GBSA binding free energy calculations/decompositions were detected and discussed. These findings suggest that the compound can be used as a good lead compound for further optimization to obtain more promising P2YR antagonists for the treatment of acute gouty arthritis.