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.
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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DOI：
10.1021/jm900611t
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发表时间：
2009-08-27
影响因子：
7.3
通讯作者：
Mesecar AD
中科院分区：
文献类型：
--
作者：
Ghosh AK;Takayama J;Aubin Y;Ratia K;Chaudhuri R;Baez Y;Sleeman K;Coughlin M;Nichols DB;Mulhearn DC;Prabhakar BS;Baker SC;Johnson ME;Mesecar AD
我们在这里描述了一系列小分子、非肽SARS-CoV PLpro抑制剂的设计、合成、分子建模和生物学评价。我们最初的先导化合物是通过高通量筛选多种化学文库确定的。我们随后进行了结构-活性关系研究，并优化了有效抑制剂的先导结构，这些抑制剂已显示出对SARS-CoV感染的Vero E6细胞的抗病毒活性。基于与SARS-CoV PLpro结合的强效抑制剂之一24的x射线晶体结构，创建了药物设计模板。我们基于结构的修饰导致设计出更有效的抑制剂2（酶IC50 = 0.46 μM，抗病毒EC50 = 12.5 μM）。有趣的是，其甲胺衍生物49在该系列中表现出良好的酶抑制效力（IC50 = 1.3 μM）和最有效的SARS抗病毒活性（EC50 = 2.5 μM）。我们进行了计算对接研究，并为SARS-CoV PLpro抑制剂生成了预测3D-QSAR模型。
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. Based upon the X-ray crystal structure of one of the potent inhibitors 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 = 12.5 μM). Interestingly, its methylamine derivative 49 displayed good enzyme inhibitory potency (IC50 = 1.3 μM) and most potent SARS antiviral activity (EC50 = 2.5 μM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.
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影响因子：
--
作者：
Ghosh, Arun K.;Xi, Kai;Johnson, Michael E.;Baker, Susan C.;Mesecar, Andrew D.
通讯作者：
Mesecar, Andrew D.
DOI：
10.1016/s0140-6736(03)13077-2
发表时间：
2003-04-19
期刊：
Lancet (London, England)
影响因子：
--
作者：
Peiris JS;Lai ST;Poon LL;Guan Y;Yam LY;Lim W;Nicholls J;Yee WK;Yan WW;Cheung MT;Cheng VC;Chan KH;Tsang DN;Yung RW;Ng TK;Yuen KY;SARS study group
通讯作者：
SARS study group
影响因子：
5.4
作者：
Lindner, HA;Fotouhi-Ardakani, N;Ménard, R
通讯作者：
Ménard, R
影响因子：
2.6
作者：
Kraszkiewicz, L;Sosnowski, M;Skulski, L
通讯作者：
Skulski, L
影响因子：
2.7
作者：
Jain, RP;Vederas, JC
通讯作者：
Vederas, JC