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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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| Authors: | 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 |
| Institution: | 1. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;2. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA;3. Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA;4. Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA;5. Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, IL 60607, USA;6. Scripps Research Institute Molecular Screening Center, Lead Identification Division, Translational Research Institute, Jupiter, FL 33458, USA;7. Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA |
| 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 Severe acute respiratory syndrome SARS MERS Coronavirus |
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