Yokokawa, Fumiaki, Noble, Christian Guy, Lim, Siew Pheng, Rao, Ranga Rao K.R., Tania, Stefani, Wang, Gang, Lee, Gladys, Hunziker, Juerg, Karuna, Ratnaningrum, Manjunatha, Ujjini Havaldar, Nilar, Shahul, 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