Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: Identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding

Mark Turlington, Aspen Chun, Sakshi Tomar, Aimee Eggler, Valerie Grum-Tokars, Jon Jacobs, J. Scott Daniels, Eric Dawson, Adrian Saldanha, Peter Chase, Yahira M. Baez-Santos, Craig W. Lindsley, Peter Hodder, Andrew D. Mesecar*, Shaun R. Stauffer

*Corresponding author for this work

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Herein we report the discovery and SAR of a novel series of SARS-CoV 3CLpro inhibitors identified through the NIH Molecular Libraries Probe Production Centers Network (MLPCN). In addition to ML188, ML300 represents the second probe declared for 3CLpro from this collaborative effort. The X-ray structure of SARS-CoV 3CLpro bound with a ML300 analog highlights a unique induced-fit reorganization of the S2-S4 binding pockets leading to the first sub-micromolar noncovalent 3CLpro inhibitors retaining a single amide bond.

Original languageEnglish (US)
Pages (from-to)6172-6177
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number22
DOIs
StatePublished - Nov 15 2013

Keywords

  • 3CLpro
  • Coronavirus
  • MERS
  • SARS
  • Severe acute respiratory syndrome

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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