期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 52, 期 16, 页码 5228-5240出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm900611t
关键词
-
资金
- Public Health Service Research Grant [P01 AI060915]
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 mu M; antiviral EC50 = 6 mu M). Interestingly. its methylamine derivative, 49, displayed good enzyme inhibitory potency (IC50 = 1.3 mu M) and the most potent SARS antiviral activity (EC50 = 5.2 mu M) in the series, We have carried our computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.
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