Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

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

Yokokawa, Fumiaki and Noble, Christian Guy and Lim, Siew Pheng and Rao, Ranga Rao K.R. and Tania, Stefani and Wang, Gang and Lee, Gladys and Hunziker, Juerg and Karuna, Ratnaningrum and Manjunatha, Ujjini Havaldar and Nilar, Shahul and Shi, Pei-Yong and Smith, Paul (2016) Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase From a Fragment Hit Using Structure-Based Drug Design. Journal of Medicinal Chemistry. ISSN 0022-26231520-4804

Abstract

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 anti-dengue 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 RdRp and exerts a promising activity against all clinically relevant dengue serotypes.

Item Type: Article
Date Deposited: 27 Apr 2016 23:45
Last Modified: 27 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/28096

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.