As a critical enzyme for the uric acid production, xanthine oxidase (XO) has emerged as a primary drug target for antihyperuricemic therapy. A hierarchical virtual screening integrating both ligand-based and structure-based approaches was applied herein to identify potent XO inhibitors. Four compounds, which were previously reported as XO inhibitors, were recognized through the virtual screening protocol, and compound H3, which is distinct from the structures of known XO inhibitors, was identified as a new chemotype inhibitor with IC50 of 2.6 μM. The binding mode of H3 was further investigated by molecular docking and molecular dynamics (MD) simulation. The results suggested the feasibility to discover new chemotypes of XO inhibitors via integrated virtual screening strategies.
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