Modeling the Binding Mechanism of Remdesivir, Favilavir, and Ribavirin to SARS-CoV-2 RNA-Dependent RNA Polymerase.
Modeling the Binding Mechanism of Remdesivir, Favilavir, and Ribavirin to SARS-CoV-2 RNA-Dependent RNA Polymerase.
复制标题
DOI：
10.1021/acscentsci.0c01242
复制
发表时间：
2021-01-27
影响因子：
18.2
通讯作者：
de Pablo JJ
中科院分区：
文献类型：
--
作者：
Byléhn F;Menéndez CA;Perez-Lemus GR;Alvarado W;de Pablo JJ
最近为对抗新冠肺炎而改变药物用途的努力已将雷姆德韦确定为候选药物。它作用于SARS-CoV-2病毒的依赖RNA的RNA聚合酶(RdRp)，这是一种负责介导病毒基因组复制的蛋白质复合体。然而，它的确切作用机制以及其他核苷酸类似物抑制剂的确切作用机制尚不清楚。在这项研究中，我们依靠原子分子模拟和高级采样，在分子水平上研究了该药物与类似核苷酸类似抑制剂利巴韦林和贝利拉韦的相互作用。通过分析这些不同药物的结合自由能，发现它们都强烈结合在活性部位。然而，令人惊讶的是，利巴韦林和贝利拉韦并不像雷米韦韦那样有效地将核苷酸结合在互补链上，而且似乎通过与瑞希韦不同的机制发挥作用。雷米西韦与天然碱基腺嘌呤具有相似的结合作用。此外，通过分析Remsivir在RNA下游的位置，我们还发现，与“延迟”终止机制一致，在添加Redesivir后，可以加入额外的核苷酸，其高极性的1‘-氰基引起一系列构象变化，从而影响正常的RdRp复合体功能。通过分析由redesivir结合改变的残基的波动，并将其与致死点突变引起的残基进行比较，我们发现了redesivir破坏蛋白质复合体及其与RNA链相互作用的可能的二级机制。通过分子模拟，阐明了核苷酸类似物抑制剂雷米昔韦、利培拉韦和利巴韦林对SARS-CoV-2 RNA依赖的RNA聚合酶的可能作用机制。
Recent efforts to repurpose drugs to combat COVID-19 have identified Remdesivir as a candidate. It acts on the RNA-dependent, RNA polymerase (RdRp) of the SARS-CoV-2 virus, a protein complex responsible for mediating replication of the virus’s genome. However, its exact action mechanism, and that of other nucleotide analogue inhibitors, is not known. In this study, we examine at the molecular level the interaction of this drug and that of similar nucleotide analogue inhibitors, ribavirin and favilavir, by relying on atomistic molecular simulations and advanced sampling. By analyzing the binding free energies of these different drugs, it is found that all of them bind strongly at the active site. Surprisingly, however, ribavirin and favilavir do not bind the nucleotide on the complementary strand as effectively and seem to act by a different mechanism than remdesivir. Remdesivir exhibits similar binding interactions to the natural base adenine. Moreover, by analyzing remdesivir at downstream positions of the RNA, we also find that, consistent with a “delayed” termination mechanism, additional nucleotides can be incorporated after remdesivir is added, and its highly polar 1′-cyano group induces a set of conformational changes that can affect the normal RdRp complex function. By analyzing the fluctuations of residues that are altered by remdesivir binding, and comparing them to those induced by lethal point mutations, we find a possible secondary mechanism in which remdesivir destabilizes the protein complex and its interactions with the RNA strands. Through molecular simulation, possible mechanisms of action of the nucleotide-analogue inhibitors remdesivir, favilavir, and ribavirin on the RNA-dependent RNA polymerase of SARS-CoV-2 are elucidated.
登录
查看更多内容
影响因子：
158.5
作者：
Li, Qun;Guan, Xuhua;Feng, Zijian
通讯作者：
Feng, Zijian
影响因子：
3.5
作者：
Klimovich, Pavel V.;Shirts, Michael R.;Mobley, David L.
通讯作者：
Mobley, David L.
影响因子：
7.7
作者：
Arba M;Wahyudi ST;Brunt DJ;Paradis N;Wu C
通讯作者：
Wu C
热力学整合中的软核电位：比较一步和两步的变换。
影响因子：
3
作者：
Steinbrecher, Thomas;Joung, InSuk;Case, David A.
通讯作者：
Case, David A.
影响因子：
3.9
作者：
通讯作者：
--