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

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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 S ₂–S ₄ binding pockets leading to the first sub-micromolar noncovalent 3CLpro inhibitors retaining a single amide bond.

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Contributors

Shaun R. Stauffer

Journal

Journal ID (nlm-ta): Bioorg Med Chem Lett

Journal ID (iso-abbrev): Bioorg. Med. Chem. Lett

Title: Bioorganic & Medicinal Chemistry Letters

Publisher: Elsevier Ltd.

ISSN (Print): 0960-894X

ISSN (Electronic): 1464-3405

Publication date PMC-release: 7 September 2013

Publication date (Print): 15 November 2013

Publication date (Electronic): 7 September 2013

Volume: 23

Issue: 22

Pages: 6172-6177

Affiliations

[a ]Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA

[b ]Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA

[c ]Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA

[d ]Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA

[e ]Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, IL 60607, USA

[f ]Scripps Research Institute Molecular Screening Center, Lead Identification Division, Translational Research Institute, Jupiter, FL 33458, USA

[g ]Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA

Author notes

[* ]Corresponding authors. shaun.stauffer@ 123456vanderbilt.edu

Article

Publisher ID: S0960-894X(13)01061-5

DOI: 10.1016/j.bmcl.2013.08.112

PMC ID: 3878165

PubMed ID: 24080461

SO-VID: f5380afb-cef6-4939-8b09-842779e0f54c

License:

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

History

Date received : 2 July 2013

Date revision received : 26 August 2013

Date accepted : 29 August 2013

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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

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