Modeling the Binding Mechanism of Remdesivir, Favilavir, and Ribavirin to SARS-CoV-2 RNA-Dependent RNA Polymerase,ACS Central Science

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Modeling the Binding Mechanism of Remdesivir, Favilavir, and Ribavirin to SARS-CoV-2 RNA-Dependent RNA Polymerase
ACS Central Science ( IF 12.7 ) Pub Date : 2021-01-06 , DOI: 10.1021/acscentsci.0c01242
Fabian Byléhn ₁ , Cintia A Menéndez ₁ , Gustavo R Perez-Lemus ₁ , Walter Alvarado _{1,

2} , Juan J de Pablo ₁

Affiliation

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.

中文翻译：

模拟瑞德西韦、法维拉韦和利巴韦林与 SARS-CoV-2 RNA 依赖性 RNA 聚合酶的结合机制

最近重新调整药物用途以对抗 COVID-19 的努力已确定瑞德西韦为候选药物。它作用于 SARS-CoV-2 病毒的 RNA 依赖性 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物。然而，其确切的作用机制以及其他核苷酸类似物抑制剂的作用机制尚不清楚。在这项研究中，我们依靠原子分子模拟和先进采样，在分子水平上检查了该药物与类似核苷酸类似物抑制剂利巴韦林和法维拉韦的相互作用。通过分析这些不同药物的结合自由能，发现它们都在活性位点处强烈结合。然而，令人惊讶的是，利巴韦林和法维拉韦不能有效地结合互补链上的核苷酸，并且似乎通过与瑞德西韦不同的机制起作用。瑞德西韦与天然碱基腺嘌呤表现出类似的结合相互作用。此外，通过分析瑞德西韦RNA下游位置，我们还发现，与“延迟”终止机制一致，添加瑞德西韦后可以掺入额外的核苷酸，其高极性的1'-氰基会诱导一组构象。可能影响正常 RdRp 复合体功能的变化。通过分析瑞德西韦结合改变的残基波动，并将其与致死点突变诱导的残基波动进行比较，我们发现了瑞德西韦破坏蛋白质复合物及其与 RNA 链相互作用的可能的二级机制。

更新日期：2021-01-27

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