Identification of potential natural inhibitors of SARS-CoV2 main protease by molecular docking and simulation studies
Identification of potential natural inhibitors of SARS-CoV2 main protease by molecular docking and simulation studies
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DOI：
10.1080/07391102.2020.1776157
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发表时间：
2020-06-09
影响因子：
4.4
通讯作者：
Kumar, Shashank
中科院分区：
文献类型：
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作者：
Gupta, Sanjay;Singh, Atul Kumar;Kumar, Shashank
冠状病毒是主要引起呼吸道和肠道感染的传染性病原体。开发抗冠状病毒药物的研究工作表明，主要蛋白酶（Mpro）蛋白可能是有效的药物靶点。SARS-CoV 2 Mpro蛋白的X-射线晶体学结构表明Glu 166、Cys 141和His 41残基参与蛋白二聚化及其催化功能。我们对姜黄中的化合物进行了电子筛选。（菊科）对Mpro蛋白抑制的作用。采用分子对接，评分功能，和分子动力学模拟相结合，267化合物进行了筛选Mpro晶体结构上的对接。对接得分和相互作用谱分析显示，化合物C1（1 E，6 E）-1，2，6，7-四羟基-1，7-双（4-羟基-3-甲氧基苯基）庚-1，6-二烯-3，5-二酮）和C2（4 Z，6 E）-1，5-二羟基-1，7-双（4-羟基苯基）庚-4，6-二烯-3-酮作为先导剂在Mpro催化结构域上具有强结合。与紫草素和洛匹那韦（一种标准的Mpro抑制剂，约为-5.4千卡/摩尔）相比，化合物C1和C2对Mpro蛋白的结合得分最低（-9.08和-8.07千卡/摩尔）。此外，主成分分析，自由能景观和蛋白质-配体能量计算研究表明，这两种化合物强烈结合的Mpro蛋白的催化核心具有更高的疗效比洛匹那韦，一个标准的抗逆转录病毒的蛋白酶抑制剂类。总之，这种基于结构的优化为两种天然Mpro抑制剂提供了先导，用于进一步测试和开发作为抗人类冠状病毒的治疗剂。作者：Ramaswamy H. Sarma
Coronaviruses are contagious pathogens primarily responsible for respiratory and intestinal infections. Research efforts to develop antiviral agents against coronavirus demonstrated the main protease (Mpro) protein may represent effective drug target. X-ray crystallographic structure of the SARS-CoV2 Mpro protein demonstrated the significance of Glu166, Cys141, and His41 residues involved in protein dimerization and its catalytic function. We performedin silicoscreening of compounds fromCurcuma longaL. (Zingiberaceae family) against Mpro protein inhibition. Employing a combination of molecular docking, scoring functions, and molecular dynamics simulations, 267 compounds were screened by docking on Mpro crystallographic structure. Docking score and interaction profile analysis exhibited strong binding on the Mpro catalytic domain with compounds C1(1E,6E)-1,2,6,7-tetrahydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione) and C2(4Z,6E)-1,5-dihydroxy-1,7-bis(4-hydroxyphenyl)hepta-4,6-dien-3-one as lead agents. Compound C1and C2showed minimum binding score (-9.08 and -8.07 kcal/mole) against Mpro protein in comparison to shikonin and lopinavir (approximate to -5.4 kcal/mole) a standard Mpro inhibitor. Furthermore, principal component analysis, free energy landscape and protein-ligand energy calculation studies revealed that these two compounds strongly bind to the catalytic core of the Mpro protein with higher efficacy than lopinavir, a standard antiretroviral of the protease inhibitor class. Taken together, this structure based optimization has provided lead on two natural Mpro inhibitors for further testing and development as therapeutics against human coronavirus. Communicated by Ramaswamy H. Sarma