Discovery of novel and potent P2Y14R antagonists via structure-based virtual screening for the treatment of acute gouty arthritis

Abstract

P2Y14 nucleotide receptor is a Gi protein-coupled receptor, which is widely involved in physiological and pathologic events. Although several P2Y14R antagonists have been developed thus far, few have successfully been developed into a therapeutic drug. In this study, on the basis of two P2Y14R homology models, Glide docking-based virtual screening (VS) strategy was employed for finding potent P2Y14R 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 P2Y14R (IC50 < 50 nM), including four compounds (compounds 8, 10, 18 and 19) with IC50 value below 10 nM. The best VS hit, compound 8 exhibited the best antagonistic activity, with IC50 value of 2.46 nM. More importantly, compound 8 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 P2Y14R-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 8 can be used as a good lead compound for further optimization to obtain more promising P2Y14R antagonists for the treatment of acute gouty arthritis. Keywords: P2Y14R, Homology modeling, Virtual screening, Molecular docking, Pyroptosis, Acute gouty arthritis