Discovery of novel and potent P2Y14R antagonists via structure-based virtual screening for the treatment of acute gouty arthritis
Weiwei Wang, Chunxiao Liu, Hanwen Li, Hanwen Li, Sheng Tian, Yingxian Liu, Nanxi Wang, Duanyang Yan, Huanqiu Li, Huanqiu Li, Qinghua Hu
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.