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

Bioorg Med Chem Lett. 2013 Nov 15;23(22):6172-7. doi: 10.1016/j.bmcl.2013.08.112. Epub 2013 Sep 7.

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.

Keywords: 3CLpro; Coronavirus; MERS; SARS; Severe acute respiratory syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry*
  • Acetamides / pharmacology*
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology*
  • Humans
  • Models, Molecular
  • Severe Acute Respiratory Syndrome / drug therapy*
  • Severe Acute Respiratory Syndrome / virology
  • Severe acute respiratory syndrome-related coronavirus / drug effects*
  • Structure-Activity Relationship

Substances

  • Acetamides
  • Antiviral Agents