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 journalArticle

32 Citations (Scopus)

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

Fingerprint

RNA Replicase
Dengue
Drug Design
Viral RNA
Acetic Acid
X-Rays
Serogroup

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design. / Yokokawa, Fumiaki; Nilar, Shahul; Noble, Christian G.; Lim, Siew Pheng; Rao, Ranga; Tania, Stefani; Wang, Gang; Lee, Gladys; Hunziker, Jürg; Karuna, Ratna; Manjunatha, Ujjini; Shi, Pei-Yong; Smith, Paul W.

In: Journal of Medicinal Chemistry, Vol. 59, No. 8, 28.04.2016, p. 3935-3952.

Research output: Contribution to journalArticle

Yokokawa, F, Nilar, S, Noble, CG, Lim, SP, Rao, R, Tania, S, Wang, G, Lee, G, Hunziker, J, Karuna, R, Manjunatha, U, Shi, P-Y & Smith, PW 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, vol. 59, no. 8, pp. 3935-3952. https://doi.org/10.1021/acs.jmedchem.6b00143
Yokokawa, Fumiaki ; Nilar, Shahul ; Noble, Christian G. ; Lim, Siew Pheng ; Rao, Ranga ; Tania, Stefani ; Wang, Gang ; Lee, Gladys ; Hunziker, Jürg ; Karuna, Ratna ; Manjunatha, Ujjini ; Shi, Pei-Yong ; Smith, Paul W. / Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 8. pp. 3935-3952.
@article{9e70ab002bc4486d8efd4f19c41f5229,
title = "Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design",
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.",
author = "Fumiaki Yokokawa and Shahul Nilar and Noble, {Christian G.} and Lim, {Siew Pheng} and Ranga Rao and Stefani Tania and Gang Wang and Gladys Lee and J{\"u}rg Hunziker and Ratna Karuna and Ujjini Manjunatha and Pei-Yong Shi and Smith, {Paul W.}",
year = "2016",
month = "4",
day = "28",
doi = "10.1021/acs.jmedchem.6b00143",
language = "English (US)",
volume = "59",
pages = "3935--3952",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "8",

}

TY - JOUR

T1 - Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design

AU - Yokokawa, Fumiaki

AU - Nilar, Shahul

AU - Noble, Christian G.

AU - Lim, Siew Pheng

AU - Rao, Ranga

AU - Tania, Stefani

AU - Wang, Gang

AU - Lee, Gladys

AU - Hunziker, Jürg

AU - Karuna, Ratna

AU - Manjunatha, Ujjini

AU - Shi, Pei-Yong

AU - Smith, Paul W.

PY - 2016/4/28

Y1 - 2016/4/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84966264850&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84966264850&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.6b00143

DO - 10.1021/acs.jmedchem.6b00143

M3 - Article

VL - 59

SP - 3935

EP - 3952

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 8

ER -