Severe Acute Respiratory Syndrome Coronavirus Papain-like Novel Protease Inhibitors: Design, Synthesis, Protein−Ligand X-ray Structure and Biological Evaluation

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• 作者：Arun K. Ghosh ; Jun Takayama ; Kalapala Venkateswara Rao ; Kiira Ratia ; Rima Chaudhuri ; Debbie C. Mulhearn ; Hyun Lee ; Daniel B. Nichols ; Surendranath Baliji ; Susan C. Baker ; Michael E. Johnson ; Andrew D.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：July 8, 2010
• 年：2010
• 卷：53
• 期：13
• 页码：4968-4979
• 全文大小：1059K
• 年卷期：v.53,no.13(July 8, 2010)
• ISSN：1520-4804

文摘

The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure−activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15h (enzyme IC₅₀ = 0.56 μM; antiviral EC₅₀ = 9.1 μM) and the corresponding (R)-Me 15g (IC₅₀ = 0.32 μM; antiviral EC₅₀ = 9.1 μM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein−ligand X-ray structure of 15g-bound SARS-CoV PLpro and a corresponding model of 15h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.