Structure-Based Design, Synthesis, and Biological Evaluation of a Series of Novel and Reversible Inhibitors for the Severe Acute Respiratory Syndrome−Coronavirus Papain-Like Protease

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• 作者：Arun K. Ghosh ; Jun Takayama ; Yoann Aubin ; Kiira Ratia ; Rima Chaudhuri ; Yahira Baez ; Katrina Sleeman ; Melissa Coughlin ; Daniel B. Nichols ; Debbie C. Mulhearn ; Bellur S. Prabhakar ; Susan C. Baker ; Micha
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：August 27, 2009
• 年：2009
• 卷：52
• 期：16
• 页码：5228-5240
• 全文大小：1042K
• 年卷期：v.52,no.16(August 27, 2009)
• ISSN：1520-4804

文摘

We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, nonpeptide inhibitors of SARS-CoV PLpro. Our initial lead compound was identified via high-throughput screening of a diverse chemical library. We subsequently carried out structure−activity relationship studies and optimized the lead structure to potent inhibitors that have shown antiviral activity against SARS-CoV infected Vero E6 cells. Upon the basis of the X-ray crystal structure of inhibitor 24-bound to SARS-CoV PLpro, a drug design template was created. Our structure-based modification led to the design of a more potent inhibitor, 2 (enzyme IC₅₀ = 0.46 μM; antiviral EC₅₀ = 6 μM). Interestingly, its methylamine derivative, 49, displayed good enzyme inhibitory potency (IC₅₀ = 1.3 μM) and the most potent SARS antiviral activity (EC₅₀ = 5.2 μM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.