Abadi Mohammad Hossein Haghir Ebrahim, Bayani Fatemeh, Sefidbakht Yahya
Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, 1983969411, Iran.
Protein Research Center, Shahid Beheshti University, Tehran, Iran.
Sci Rep. 2025 Jul 1;15(1):20500. doi: 10.1038/s41598-025-05375-5.
The viral main protease is a critical drug target due to its role in the SARS-CoV-2 life cycle. In this study, we evaluated 2,000 potential Mpro inhibitors recommended by the FragRep server, with a focus on interactions with the CYS145 residue. Six top candidates were selected for each of the 7JKV and 7TDU Mpro structures, and covalent molecular docking was performed using SeeSAR. We docked twelve ligands to various Mpro sites and performed 100 ns molecular dynamics (MD) simulations on the highest-scoring ligands: lig-14-23, lig-6-32, lig-2-3, lig-0101, lig-7612, lig-811, and lig-837. MD analysis, including Root Mean Square Deviation (RMSD), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), and Root Mean Square Fluctuation (RMSF), confirmed the stability of the covalent complexes. Non-covalent ligands, which exhibited higher toxicity profiles, were excluded from the molecular dynamics analysis. The results indicate that lig-7612 and lig-837 form stable interactions with Mpro, suggesting their potential as drug candidates. These inhibitors exhibit pharmacological properties that could influence drug interactions and metabolism in vivo. Further safety and pharmacokinetic assessments are required for therapeutic development.
病毒主蛋白酶因其在SARS-CoV-2生命周期中的作用而成为关键的药物靶点。在本研究中，我们评估了FragRep服务器推荐的2000种潜在Mpro抑制剂，重点关注与CYS145残基的相互作用。针对7JKV和7TDU Mpro结构分别选出了6个顶级候选物，并使用SeeSAR进行了共价分子对接。我们将12种配体对接至各种Mpro位点，并对得分最高的配体（lig-14-23、lig-6-32、lig-2-3、lig-0101、lig-7612、lig-811和lig-837）进行了100 ns的分子动力学（MD）模拟。包括均方根偏差（RMSD）、回转半径（Rg）、溶剂可及表面积（SASA）和均方根波动（RMSF）在内的MD分析证实了共价复合物的稳定性。具有较高毒性特征的非共价配体被排除在分子动力学分析之外。结果表明，lig-7612和lig-837与Mpro形成稳定的相互作用，表明它们作为候选药物的潜力。这些抑制剂具有可能影响体内药物相互作用和代谢的药理学特性。治疗性开发还需要进一步的安全性和药代动力学评估。
