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

Graphical abstract
Highlights • A reliable Glide docking-based virtual screening (VS) pipeline for P2Y14R was developed. • Several potent P2Y14R antagonists with novel scaffolds were identified utilizing the VS strategy. • P2Y14R inhibitory effect was evaluated by testing cAMP levels in HEK293 cells. • Anti-gout activity of screened compound was detected in MSU-treated THP-1 cells. • The mechanism of test compound in treating acute gouty arthritis was elucidated.
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