Abstract

This work aimed at evaluating the inhibitory effect of ten natural bioactive compounds (1–10) as potential inhibitors of SARS-CoV-2-3CL main protease (PDB ID: 6LU7) and SARS-CoV main proteases (PDB IDs: 2GTB and 3TNT) by molecular docking analysis. The inhibitory effect of all studied compounds was studied with compared to some proposed antiviral drugs which currently used in COVID-19 treatment such as chloroquine, hydroxychloroquine, azithromycin, remdesivir, baloxvir, lopinavir, and favipiravir. Homology modeling and sequence alignment was computed to evaluate the similarity between the SARS-CoV-2-3CL main protease and other SARS-CoV receptors. ADMET properties of all studied compounds were computed and reported. Also, molecular dynamic (MD) simulation was performed on the compound which has the highest binding affinity inside 6LU7 obtained from molecular docking analysis to study it is stability inside receptor in explicit water solvent. Based on molecular docking analysis, we found that caulerpin has the highest binding affinity inside all studied receptors compared to other bioactive compounds and studied drugs. Our homology modeling and sequence alignment showed that SARS-CoV main protease (PDB ID: 3TNT) shares high similarity with 3CLpro (96.00%). Also, ADMET properties confirmed that caulerpin obeys Lipinski’s rule and passes ADMET property, which make it a promising compound to act as a new safe natural drug against SARS-CoV-2-3CL main protease. Finally, MD simulation confirmed that the complex formed between caulerpin and 3CLpro is stable in water explicit and had no major effect on the flexibility of the protein throughout the simulations and provided a suitable basis for our study. Also, binding free energy between caulerpin and 6LU7 confirmed the efficacy of the caulerpin molecule against SARS-CoV-2 main protease. So, this study suggested that caulerpin could be used as a potential candidate in COVID-19 treatment.

 抽象的

这项工作旨在评估十种天然生物活性化合物（1-10）作为 SARS-CoV-2-3CL 主要蛋白酶（PDB ID：6LU7）和 SARS-CoV 主要蛋白酶（PDB ID：2GTB 和 3TNT）潜在抑制剂的抑制作用）通过分子对接分析。研究了所有研究化合物的抑制作用，并与目前用于 COVID-19 治疗的一些拟议抗病毒药物（例如氯喹、羟氯喹、阿奇霉素、瑞德西韦、巴洛克斯韦、洛匹那韦和法匹拉韦）进行了比较。计算同源建模和序列比对，以评估 SARS-CoV-2-3CL 主要蛋白酶与其他 SARS-CoV 受体之间的相似性。计算并报告了所有研究化合物的 ADMET 特性。此外，对分子对接分析中获得的6LU7内部结合亲和力最高的化合物进行分子动力学（MD）模拟，以研究其在显式水溶剂中受体内部的稳定性。基于分子对接分析，我们发现与其他生物活性化合物和研究的药物相比，caulerpin在所有研究的受体内具有最高的结合亲和力。我们的同源建模和序列比对表明，SARS-CoV 主要蛋白酶（PDB ID：3TNT）与 3CLpro 具有高度相似性（96.00%）。此外，ADMET 特性证实，caulerpin 遵循 Lipinski 规则并通过 ADMET 特性，这使其成为一种有前景的化合物，可作为对抗 SARS-CoV-2-3CL 主要蛋白酶的新型安全天然药物。最后，MD模拟证实，caulerpin和3CLpro形成的复合物在水中稳定，并且在整个模拟过程中对蛋白质的灵活性没有重大影响，为我们的研究提供了合适的基础。 此外，caulerpin 和 6LU7 之间的结合自由能证实了 caulerpin 分子对抗 SARS-CoV-2 主要蛋白酶的功效。因此，这项研究表明 caulerpin 可以作为 COVID-19 治疗的潜在候选药物。