Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design

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• 作者：Fumiaki Yokokawa ; Shahul Nilar ; Christian G. Noble ; Siew Pheng Lim ; Ranga Rao ; Stefani Tania ; Gang Wang ; Gladys Lee ; Jürg Hunziker ; Ratna Karuna ; Ujjini Manjunatha ; Pei-Yong Shi ; Paul W. Smith
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 28, 2016
• 年：2016
• 卷：59
• 期：8
• 页码：3935-3952
• 全文大小：860K
• 年卷期：0
• ISSN：1520-4804

文摘

The discovery and optimization of non-nucleoside dengue viral RNA-dependent-RNA polymerase (RdRp) inhibitors are described. An X-ray-based fragment screen of Novartis’ fragment collection resulted in the identification of a biphenyl acetic acid fragment 3, which bound in the palm subdomain of RdRp. Subsequent optimization of the fragment hit 3, relying on structure-based design, resulted in a >1000-fold improvement in potency in vitro and acquired antidengue activity against all four serotypes with low micromolar EC₅₀ in cell-based assays. The lead candidate 27 interacts with a novel binding pocket in the palm subdomain of the RdRp and exerts a promising activity against all clinically relevant dengue serotypes.