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SARS-CoV-2 解旋酶 Nsp13 的潜在植物化学抑制剂:分子对接和动态模拟研究。

Potential phytochemical inhibitors of SARS-CoV-2 helicase Nsp13: a molecular docking and dynamic simulation study.

机构信息

The Institute of Mathematical Sciences (IMSc), Chennai, 600113, India.

Homi Bhabha National Institute (HBNI), Mumbai, 400094, India.

出版信息

Mol Divers. 2022 Feb;26(1):429-442. doi: 10.1007/s11030-021-10251-1. Epub 2021 Jun 12.

Abstract

The SARS-CoV-2 helicase Nsp13 is a promising target for developing anti-COVID drugs. In the present study, we have identified potential natural product inhibitors of SARS-CoV-2 Nsp13 targeting the ATP-binding site using molecular docking and molecular dynamics (MD) simulations. MD simulation of the prepared crystal structure of SARS-CoV-2 Nsp13 was performed to generate an ensemble of structures of helicase Nsp13 capturing the conformational diversity of the ATP-binding site. A natural product library of more than 14,000 phytochemicals from Indian medicinal plants was used to perform virtual screening against the ensemble of Nsp13 structures. Subsequently, a two-stage filter, first based on protein-ligand docking binding energy value and second based on protein residues in the ligand-binding site and non-covalent interactions between the protein residues and the ligand in the best-docked pose, was used to identify 368 phytochemicals as potential inhibitors of SARS-CoV-2 helicase Nsp13. MD simulations of the top inhibitors complexed with protein were performed to confirm stable binding, and to compute MM-PBSA based binding energy. From among the 368 potential phytochemical inhibitors, the top identified potential inhibitors of SARS-CoV-2 helicase Nsp13 namely, Picrasidine M, (+)-Epiexcelsin, Isorhoeadine, Euphorbetin and Picrasidine N, can be taken up initially for experimental studies.

摘要

新型冠状病毒 2 型螺旋酶 Nsp13 是开发抗 COVID 药物的有前途的靶标。在本研究中,我们使用分子对接和分子动力学(MD)模拟,针对 ATP 结合位点,鉴定了针对新型冠状病毒 2 型 Nsp13 的潜在天然产物抑制剂。对新型冠状病毒 2 型 Nsp13 的制备晶体结构进行 MD 模拟,以生成捕捉 ATP 结合位点构象多样性的螺旋酶 Nsp13 结构集合。使用来自印度药用植物的超过 14000 种植物化学物质的天然产物文库对 Nsp13 结构集合进行虚拟筛选。随后,使用基于蛋白-配体对接结合能值的两阶段过滤器,其次是基于配体结合位点中的蛋白残基和最佳对接构象中蛋白残基与配体之间的非共价相互作用的过滤器,鉴定了 368 种植物化学物质作为新型冠状病毒 2 型螺旋酶 Nsp13 的潜在抑制剂。对与蛋白复合的前 368 种抑制剂进行 MD 模拟,以确认稳定结合,并计算基于 MM-PBSA 的结合能。在 368 种潜在的植物化学抑制剂中,鉴定出的新型冠状病毒 2 型螺旋酶 Nsp13 的前 5 种潜在抑制剂,即 Picrasidine M、(+)-Epiexcelsin、Isorhoeadine、Euphorbetin 和 Picrasidine N,可以首先进行实验研究。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4a4/8196922/83249f2862a1/11030_2021_10251_Fig1_HTML.jpg

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