Molecular characterization of ebselen binding activity to SARS-CoV-2 main protease
Molecular characterization of ebselen binding activity to SARS-CoV-2 main protease
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DOI：
10.1126/sciadv.abd0345
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发表时间：
2020-09-01
期刊：
影响因子：
13.6
通讯作者：
de Pablo, Juan J.
中科院分区：
文献类型：
--
作者：
Menendez, Cintia A.;Bylehn, Fabian;de Pablo, Juan J.
迫切需要重新调整抗严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的药物。最近的计算实验筛选已经确定了几种现有药物，可以作为病毒主要蛋白酶 M-pro 的有效抑制剂，M-pro 参与基因表达和复制。其中，依布硒啉（2-苯基-1,2-苯并硒唑-3-酮）似乎特别有前途。在这里，我们在分子水平上研究了依布硒啉降低 Mpro 活性的潜力。我们发现它对催化区域表现出独特的亲和力。我们的结果揭示了位于蛋白质 II 和 III 结构域之间的更高亲和力、以前未知的结合位点。详细的应变分析表明，在这样的位点上，依布硒啉发挥了显着的变构效应，通过表面环相互作用调节催化位点的进入，从而诱导水热点的重新配置。总之，这些发现凸显了依布硒啉作为抗 SARS-CoV-2 药物的前景。
There is an urgent need to repurpose drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent computational-experimental screenings have identified several existing drugs that could serve as effective inhibitors of the virus' main protease, M-pro, which is involved in gene expression and replication. Among these, ebselen (2-phenyl-1,2-benzoselenazol-3-one) appears to be particularly promising. Here, we examine, at a molecular level, the potential of ebselen to decrease Mpro activity. We find that it exhibits a distinct affinity for the catalytic region. Our results reveal a higher-affinity, previously unknown binding site localized between the II and III domains of the protein. A detailed strain analysis indicates that, on such a site, ebselen exerts a pronounced allosteric effect that regulates catalytic site access through surface-loop interactions, thereby inducing a reconfiguration of water hotspots. Together, these findings highlight the promise of ebselen as a repurposed drug against SARS-CoV-2.