Mechanistic insight on the remdesivir binding to RNA-Dependent RNA polymerase (RdRp) of SARS-cov-2.
Mechanistic insight on the remdesivir binding to RNA-Dependent RNA polymerase (RdRp) of SARS-cov-2.
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DOI：
10.1016/j.compbiomed.2020.104156
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发表时间：
2021-03
影响因子：
7.7
通讯作者：
Wu C
中科院分区：
文献类型：
--
作者：
Arba M;Wahyudi ST;Brunt DJ;Paradis N;Wu C
RNA依赖的RNA聚合酶（RdRp）是调控SARS冠状病毒复制的关键酶。Remdesivir（RDV）是临床上使用的靶向RdRp的药物，但其作用机制仍不清楚。采用分子动力学（MD）模拟方法研究了活性化合物Remdesivir-triphosphate（RDV-TP）与RdRp的结合动力学。我们使用RdRp丙型肝炎病毒和最近的SARS-CoV-2结构建立了RdRp沿着RNA和锰离子的同源性模型。我们确定该模型在500 ns MD模拟期间是稳定的。然后，我们采用该模型来研究在三个独立的500 ns MD模拟过程中RDV-TP与RdRp的结合。结果表明，蛋白质与模板-引物RNA的相互作用主要是与RNA磷酸基团的盐桥作用，而与模板-引物RNA碱基对的相互作用很小。RDV-TP的结合表明磷酸基团位于NTP通道的入口处，并通过与K551、R553和K621的相互作用而稳定，而RDV-TP上的腺苷基团则与模板链的U2配对。锰离子位于D 618、D 760和D 761附近，并且有助于RDV-TP的磷酸基团的稳定。此外，我们从天然产物数据库中鉴定了三个命中物，其与RDV-TP相似，但结合能低于RDV-TP，并且SN 00359915的结合自由能比RDV-TP低约三倍。建立了RdRp、RNA和锰离子的同源模型。Remdesivir对接到RdRp，并且对于500 ns MD模拟是稳定的。通过与关键残基的相互作用来稳定Remdesivir的结合。三个命中具有比remdesivir更低的结合能。
The RNA-dependent RNA polymerase (RdRp) is a key enzyme which regulates the viral replication of SARS-CoV-2. Remdesivir (RDV) is clinically used drug which targets RdRp, however its mechanism of action remains elusive. This study aims to find out the binding dynamics of active Remdesivir-triphosphate (RDV-TP) to RdRp by means of molecular dynamics (MD) simulation. We built a homology model of RdRp along with RNA and manganese ion using RdRp hepatitis C virus and recent SARS-CoV-2 structures. We determined that the model was stable during the 500 ns MD simulations. We then employed the model to study the binding of RDV-TP to RdRp during three independent 500 ns MD simulations. It was revealed that the interactions of protein and template-primer RNA were dominated by salt bridge interactions with phosphate groups of RNA, while interactions with base pairs of template-primer RNA were minimal. The binding of RDV-TP showed that the position of phosphate groups was at the entry of the NTP channel and it was stabilized by the interactions with K551, R553, and K621, while the adenosine group on RDV-TP was pairing with U2 of the template strand. The manganese ion was located close to D618, D760, and D761, and helps in stabilization of the phosphate groups of RDV-TP. Further we identified three hits from the natural product database that pose similar to RDV-TP while having lower binding energies than that of RDV-TP, and that SN00359915 had binding free energy about three times lower than that of RDV-TP. A homology model of RdRp, RNA, and manganese ion was built. Remdesivir was docked to RdRp and was stable for 500 ns MD simulations. The binding of remdesivir was stabilized by the interactions with key residues. Three hits had lower binding energies than that of remdesivir.
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