Mechanism of inhibition of SARS-CoV-2 M(pro) by N3 peptidyl Michael acceptor explained by QM/MM simulations and design of new derivatives with tunable chemical reactivity.
Mechanism of inhibition of SARS-CoV-2 M(pro) by N3 peptidyl Michael acceptor explained by QM/MM simulations and design of new derivatives with tunable chemical reactivity.
复制标题
N3肽基迈克尔受体对SARS-COV-2 M（Pro）抑制的机理，该机制由QM/MM模拟解释，并设计具有可调化学反应性的新衍生物。
DOI：
10.1039/d0sc06195f
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发表时间：
2020-11-27
期刊：
影响因子：
8.4
通讯作者：
Moliner V
中科院分区：
文献类型：
--
作者：
Arafet K;Serrano-Aparicio N;Lodola A;Mulholland AJ;González FV;Świderek K;Moliner V
SARS-CoV-2的主要蛋白酶（Mpro）对于导致COVID-19大流行的病毒复制至关重要，也是药物设计的主要目标之一。在这里，我们模拟抑制过程中的SARS-CoV-2 Mpro与已知的迈克尔受体（肽基）抑制剂，N3。用QM/MM分子动力学方法计算了共价酶抑制剂产物形成机制的自由能景观。模拟结果显示了一个两步机制，并给出了结构和计算的势垒与实验符合得很好。利用这些结果和信息，从我们以前的调查SARS-CoV-2 Mpro的蛋白水解反应，我们设计了两个新的，合成可访问的N3-类似物作为潜在的抑制剂，其中的识别和弹头图案进行了修改。这些新型化合物抑制Mpro机制的QM/MM建模表明，两者都可能是有希望的候选药物，一种是不可逆抑制剂，一种是潜在的可逆抑制剂。QM/MM模拟确定了N3的反应机制，N3是SARS-CoV-2主要蛋白酶的共价肽基抑制剂。两种新的化合物B1和B2的建模表明，共价抑制的可逆性可以定制。
The SARS-CoV-2 main protease (Mpro) is essential for replication of the virus responsible for the COVID-19 pandemic, and one of the main targets for drug design. Here, we simulate the inhibition process of SARS-CoV-2 Mpro with a known Michael acceptor (peptidyl) inhibitor, N3. The free energy landscape for the mechanism of the formation of the covalent enzyme-inhibitor product is computed with QM/MM molecular dynamics methods. The simulations show a two-step mechanism, and give structures and calculated barriers in good agreement with experiment. Using these results and information from our previous investigation on the proteolysis reaction of SARS-CoV-2 Mpro, we design two new, synthetically accessible N3-analogues as potential inhibitors, in which the recognition and warhead motifs are modified. QM/MM modelling of the mechanism of inhibition of Mpro by these novel compounds indicates that both may be promising candidates as drug leads against COVID-19, one as an irreversible inhibitor and one as a potential reversible inhibitor. QM/MM simulations identify the mechanism of reaction of N3, a covalent peptidyl inhibitor of SARS-CoV-2 main protease. Modelling of two novel proposed compounds, B1 and B2, suggests that reversibility of covalent inhibition could be tailored.
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影响因子：
2.9
作者：
Arafet, Kemel;Ferrer, Silvia;Moliner, Vicent
通讯作者：
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影响因子：
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