Department of Chemistry, Faculty of Education, Van Yuzuncu Yil University, Van, 65080, Turkey.
Curr Comput Aided Drug Des. 2022;18(5):337-346. doi: 10.2174/1573409918666220816113516.
The COVID-19 pandemic emerged at the end of 2019 in China and spread rapidly all over the world. Scientists strive to find virus-specific antivirals against COVID-19 disease. This study aimed to assess some flavolignans as potential SARS-CoV-2 main protease (SARS-CoV-2 Mpro) inhibitors using molecular docking study, molecular dynamic simulations, and ADME analysis.
The detailed interactions between the flavolignans and SARS-CoV-2 Mpro were determined using Autodock 4.2 software. SARS-CoV-2 Mpro was docked with selected flavolignans, and the docking results were analyzed by Autodock 4.2 and Biovia Discovery Studio 4.5. The SARS-CoV-2 Mpro-flavolignans' complexes were subjected to molecular dynamic (MD) simulations for a period of 50 ns. To measure the stability, flexibility, and average distance between the SARS-CoV-2 Mpro and flavolignans, root mean square deviations (RMSD) and root mean square fluctuation (RMSF) were calculated, and the binding free energy calculations of SARS-CoV-2 Mpro-flavolignans complexes were found to using the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) method. SwissADME web tools were used to evaluate ADME properties and pharmacokinetic parameters of the flavolignans.
The binding energies of the SARS-CoV-2 Mpro- flavolignans' complexes were identified from the molecular docking of SARS-CoV-2 Mpro. Sinaiticin was found to be the highest binding affinity of -9.4 kcal/mol and formed π-lone pair and pi-alkyl interactions with the catalytic binding residues Glu166 and Cys145. Silychristin, Dehydrosilybin, Hydrocarpin, Silydianin, and 5'- metoxyhydcaprin also showed high binding affinities of -9.3, -9.2, -9.0, -8.7 and -8.6 kcal/mol, respectively. The flavolignans demonstrated strong Carbon H bond interactions with the binding site residues of the Gln192, Gly143, Leu27, Glu166, and Tyr54, and thereby can act as potent inhibitors of the SARS-CoV 2 Mpro.
The selected flavolignans obey Lipinski's rule of five. According to the results obtained from molecular docking studies, molecular dynamic simulations, and ADME analysis, it can be proposed that the flavolignans, which can be used to design effective antiviral drug candidates against the SARS-CoV-2, can be tried for promising and effective inhibitors of the SARS-CoV-2 main protease in vitro and in vivo studies.
2019 年底，新型冠状病毒（COVID-19）在中国爆发，并迅速在全球范围内传播。科学家们努力寻找针对 COVID-19 疾病的病毒特异性抗病毒药物。本研究旨在通过分子对接研究、分子动力学模拟和 ADME 分析评估一些类黄酮作为潜在的 SARS-CoV-2 主要蛋白酶（SARS-CoV-2 Mpro）抑制剂。
使用 Autodock 4.2 软件确定类黄酮与 SARS-CoV-2 Mpro 之间的详细相互作用。将 SARS-CoV-2 Mpro 与选定的类黄酮对接，并使用 Autodock 4.2 和 Biovia Discovery Studio 4.5 分析对接结果。对 SARS-CoV-2 Mpro-类黄酮复合物进行为期 50ns 的分子动力学（MD）模拟。为了测量 SARS-CoV-2 Mpro 与类黄酮之间的稳定性、灵活性和平均距离，计算了均方根偏差（RMSD）和均方根波动（RMSF），并使用分子力学/泊松-玻尔兹曼表面面积（MM-PBSA）方法计算了 SARS-CoV-2 Mpro-类黄酮复合物的结合自由能。使用 SwissADME 网络工具评估类黄酮的 ADME 性质和药代动力学参数。
从 SARS-CoV-2 Mpro 的分子对接中确定了 SARS-CoV-2 Mpro-类黄酮复合物的结合能。发现白杨素具有最高的结合亲和力为-9.4kcal/mol，并与催化结合残基 Glu166 和 Cys145 形成π-孤对和π-烷基相互作用。水飞蓟宾、脱水水飞蓟宾、水飞蓟宁、水飞蓟宾甲醚和 5'-甲氧基水飞蓟宾也表现出较高的结合亲和力，分别为-9.3、-9.2、-9.0、-8.7 和-8.6kcal/mol。类黄酮与 Gln192、Gly143、Leu27、Glu166 和 Tyr54 的结合位点残基表现出强烈的碳氢键相互作用，因此可以作为 SARS-CoV2 Mpro 的有效抑制剂。
所选类黄酮符合 Lipinski 的五规则。根据分子对接研究、分子动力学模拟和 ADME 分析的结果，可以提出类黄酮可以作为设计针对 SARS-CoV-2 的有效抗病毒药物候选物的依据，并且可以在体外和体内研究中尝试作为 SARS-CoV-2 主要蛋白酶的有前途和有效的抑制剂。
