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

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

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)3935-3952
Number of pages18
JournalJournal of medicinal chemistry
Volume59
Issue number8
DOIs
StatePublished - Apr 28 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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