Yang Ying, Zhang Lei, Tian Jinying, Ye Fei, Xiao Zhiyan
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College Beijing 100050 China
Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College Beijing 100050 China.
RSC Adv. 2020 Jul 24;10(46):27752-27763. doi: 10.1039/d0ra03143g. eCollection 2020 Jul 21.
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 IC 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 integrated virtual screening strategies.
作为尿酸生成的关键酶，黄嘌呤氧化酶（XO）已成为抗高尿酸血症治疗的主要药物靶点。本文应用了一种结合基于配体和基于结构方法的分层虚拟筛选，以鉴定强效的XO抑制剂。通过虚拟筛选方案识别出四种先前报道为XO抑制剂的化合物，并且与已知XO抑制剂结构不同的化合物H3被鉴定为一种新的化学型抑制剂，其IC50为2.6 μM。通过分子对接和分子动力学（MD）模拟进一步研究了H3的结合模式。结果表明，整合虚拟筛选策略发现XO抑制剂新化学型具有可行性。
