"Teaching old drugs to kill new bugs": structure-based discovery of anti-SARS drugs
"Teaching old drugs to kill new bugs": structure-based discovery of anti-SARS drugs
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DOI：
10.1016/j.bbrc.2004.06.155
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发表时间：
2004-08-20
影响因子：
3.1
通讯作者：
Pattabiraman, N
中科院分区：
文献类型：
--
作者：
Rajnarayanan, RV;Dakshanamurthy, S;Pattabiraman, N
严重急性呼吸综合征（SARS）的主要蛋白酶或3C样蛋白酶（3CLpro）是冠状病毒生命周期繁殖所必需的，被认为是基于结构的抗SARS药物设计的主要靶标之一。这是一种有吸引力的方法来寻找旧药物的新用途，因为它们已经通过了广泛的临床测试，并且可以很容易地加速临床批准。简单地说，我们进行了针对SARS 3CLpro的小分子数据库的虚拟筛选，分析了抑制剂蛋白酶复合物，并鉴定了几种共价和非共价抑制剂。选择了几种与SARS 3CL原活性位点结合的旧药物，并通过计算机衍生化产生具有增强亲和力的共价不可逆抑制剂。此外，我们表明，药效团来自集群的化合物产生的虚拟筛选可能是有用的探针，为未来的结构-活性关系研究（SAR）和微调的铅分子确定。(C)2004年爱思唯尔公司All rights reserved.
Severe acute respiratory syndrome (SARS) main protease or 3C-like protease (3CLpro) is essential for the propagation of the coronaviral life cycle and is regarded as one of the main targets for structure-based anti-SARS drug design. It is an attractive approach to find new uses for old drugs as they have already been through extensive clinical testing and could easily be accelerated for clinical approval. Briefly, we performed virtual screening of a database of small molecules against SARS 3CLpro, analyzed inhibitor protease complexes, and identified several covalent and non-covalent inhibitors. Several old drugs that bind to SARS 3CLpro active site were selected and in silico derivatized to generate covalent irreversible inhibitors with enhanced affinity. Furthermore, we show that pharmacophores derived from clusters of compounds resulting out of virtual screening could be useful probes for future structure-activity relationship studies (SARs) and fine-tune the lead molecules identified. (C) 2004 Elsevier Inc. All rights reserved.