Identification of novel isocytosine derivatives as xanthine oxidase inhibitors from a set of virtual screening hits

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• 作者：Chandrika B-Rao^a ; ^{chandrika.rao@piramal.com} ; Asha Kulkarni-Almeida^b ; Kamlesh V. Katkar^b ; Smriti Khanna^a ; Usha Ghosh^c ; Ashish Keche^c ; Pranay Shah^c ; Ankita Srivastava^b ; Vaidehi Korde^a ; Kumar V.S. Nemmani^d ; Nitin J. Deshmukh^d ; Amol Dixit^d ; Manoja K. Brahma^d ; Umakant Bahirat^d ; Lalit Doshi^d ; Rajiv Sharma^c ; H. Sivaramakrishnan^c
• 关键词：XO ; xanthine oxidase ; XOI ; xanthine oxidase inhibitor ; po ; per oral ; ip ; intraperitoneal ; Mo-Pt ; molybdopterin ; PASS ; Prediction of Activity Spectra of Substances ; AUC ; area under curve ; XDH ; xanthine dehydrogenase
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 May, 2012
• 卷：20
• 期：9
• 页码：2930-2939
• 文件大小：1387 K

摘要

In recent years, xanthine oxidase has emerged as an important target not only for gout but also for cardiovascular and metabolic disorders involving hyperuricemia. Contrary to popular belief, recent clinical trials with uricosurics have demonstrated that enhanced excretion of uric acid is, by itself, not adequate to treat hyperuricemia; simultaneous inhibition of production of uric acid by inhibition of xanthine oxidase is also important. Virtual screening of in-house synthetic library followed by in vitro and in vivo testing led to the identification of a novel scaffold for xanthine oxidase inhibition. In vitro activity results corroborated the results from molecular docking studies of the virtual screening hits. The isocytosine scaffold maintains key hydrogen bonding and pi-stacking interactions in the deep end of the xanthine-binding pocket, which anchors it in an appropriate pose to inhibit binding of xanthine and shows promise for further lead optimization using structure-based drug design approach.