Inhibitors of SARS-3CLpro: Virtual Screening, Biological Evaluation, and Molecular Dynamics Simulation Studies

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• 作者：Prasenjit Mukherjee ; Falgun Shah ; Prashant Desai ; Mitchell Avery
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2011
• 出版时间：June 27, 2011
• 年：2011
• 卷：51
• 期：6
• 页码：1376-1392
• 全文大小：1496K
• 年卷期：v.51,no.6(June 27, 2011)
• ISSN：1549-960X

文摘

SARS-CoV from the coronaviridae family has been identified as the etiological agent of Severe Acute Respiratory Syndrome (SARS), a highly contagious upper respiratory disease that reached epidemic status in 2002. SARS-3CL^pro, a cysteine protease indispensible to the viral life cycle, has been identified as one of the key therapeutic targets against SARS. A combined ligand and structure-based virtual screening was carried out against the Asinex Platinum collection. Multiple low micromolar inhibitors of the enzyme were identified through this search, one of which also showed activity against SARS-CoV in a whole cell CPE assay. Furthermore, multinanosecond explicit solvent simulations were carried out using the docking poses of the identified hits to study the overall stability of the binding site interactions as well as identify important changes in the interaction profile that were not apparent from the docking study. Cumulative analysis of the evaluated compounds and the simulation studies led to the identification of certain protein鈥搇igand interaction patterns which would be useful in further structure based design efforts.