Evaluation of inhibition effect and interaction mechanism of antiviral drugs on main protease of novel coronavirus: Molecular docking and molecular dynamics studies

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling Pub Date : 2024-09-24 DOI:10.1016/j.jmgm.2024.108873

Xin Gao , Cuihong Wang , Yue Jiang , Shouchao Zhang , Meiling Zhang , Lijuan Liu , Sendan Gao

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Abstract

The outbreak of pneumonia caused by the novel coronavirus (SARS-CoV-2) has presented a challenge to public health. The identification and development of effective antiviral drugs is essential. The main protease (3CLpro) plays an important role in the viral replication of SARS-CoV-2 and is considered to be an effective therapeutic target. In this study, according to the principle of drug repurposing, a variety of antiviral drugs commonly used were studied by molecular docking and molecular dynamics (MD) simulations to obtain potential inhibitors of main proteases. 24 antiviral drugs were docked with 5 potential action sites of 3CLpro, and the drugs with high binding strength were further simulated by MD and the molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) binding free energy calculations. The results showed that the drugs with high flexibility could bind to 3CLpro better than those with low flexibility. The interaction mechanism between antiviral drugs and main protease was analyzed in detail by calculating the root mean square displacement (RMSD), root mean square fluctuation (RMSF) and interaction residues properties. The results showed that the six drugs with high flexibility (Remdesivir, Simnotrelvir, Sofosbuvir, Ledipasvir, Indinavir and Raltegravir) had strong binding strength with 3CLpro, and the last four antiviral drugs can be used as potential candidates for main protease inhibitors.

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评价抗病毒药物对新型冠状病毒主要蛋白酶的抑制作用和相互作用机制分子对接和分子动力学研究

新型冠状病毒（SARS-CoV-2）引起的肺炎疫情给公共卫生带来了挑战。确定和开发有效的抗病毒药物至关重要。主要蛋白酶（3CLpro）在 SARS-CoV-2 病毒复制过程中起着重要作用，被认为是有效的治疗靶点。本研究根据药物再利用的原则，通过分子对接和分子动力学（MD）模拟研究了多种常用的抗病毒药物，以获得主要蛋白酶的潜在抑制剂。24种抗病毒药物与3CLpro的5个潜在作用位点进行了对接，并对结合强度高的药物进一步进行了MD模拟和分子力学泊松-玻尔兹曼表面积（MM-PBSA）结合自由能计算。结果表明，灵活性高的药物比灵活性低的药物更能与 3CLpro 结合。通过计算均方根位移（RMSD）、均方根波动（RMSF）和相互作用残基特性，详细分析了抗病毒药物与主蛋白酶的相互作用机制。结果表明，高柔韧性的六种药物（雷米替韦、辛诺雷韦、索非布韦、来替帕韦、茚地那韦和雷替格韦）与3CLpro的结合强度较强，后四种抗病毒药物可作为主蛋白酶抑制剂的潜在候选药物。

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来源期刊

Journal of molecular graphics & modelling 生物-计算机：跨学科应用

CiteScore

5.50

自引率

6.90%

发文量

216

审稿时长

35 days

期刊介绍： The Journal of Molecular Graphics and Modelling is devoted to the publication of papers on the uses of computers in theoretical investigations of molecular structure, function, interaction, and design. The scope of the journal includes all aspects of molecular modeling and computational chemistry, including, for instance, the study of molecular shape and properties, molecular simulations, protein and polymer engineering, drug design, materials design, structure-activity and structure-property relationships, database mining, and compound library design. As a primary research journal, JMGM seeks to bring new knowledge to the attention of our readers. As such, submissions to the journal need to not only report results, but must draw conclusions and explore implications of the work presented. Authors are strongly encouraged to bear this in mind when preparing manuscripts. Routine applications of standard modelling approaches, providing only very limited new scientific insight, will not meet our criteria for publication. Reproducibility of reported calculations is an important issue. Wherever possible, we urge authors to enhance their papers with Supplementary Data, for example, in QSAR studies machine-readable versions of molecular datasets or in the development of new force-field parameters versions of the topology and force field parameter files. Routine applications of existing methods that do not lead to genuinely new insight will not be considered.