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

45 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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