AbouYoussef Mohamed L, Aboelnga Mohamed M, Hanafy Nemany A, El-Kelany Khaled E
Institute of Nanoscience and Nanotechnology, Kafrelshiekh University, Kafrelskiekh, 33516, Egypt.
Chemistry Department, Faculty of Science, Damietta University, New Damietta, 34511, Egypt.
Sci Rep. 2025 Jun 23;15(1):20260. doi: 10.1038/s41598-025-06676-5.
The global pandemic caused by SARS-CoV-2 has underscored the critical necessity for effective antiviral therapies. The viral main protease (Mpro), crucial for viral replication, has emerged as a promising therapeutic target. In the present study, the inhibitory potential of ten drug-like compounds (KL1-KL10), designed as derivatives of the parent inhibitor K36, against Mpro, has been computationally investigated. To elucidate the binding affinities and interactions of the suggested drugs with the Mpro active site, molecular docking and molecular dynamics (MD) simulations till 500 nanoseconds have been applied. Our results revealed that many suggested inhibitors exhibited enhanced binding affinities compared to the parent inhibitor K36. Among these, KL7 displayed the most favourable binding characteristics, with a docking score of -13.54 and MM-PBSA binding energy of -34.57 kJ/mol, surpassing that of K36. Molecular dynamics simulations demonstrated persistent binding of these compounds to Mpro, with RMSD values ranging from 0.5 to 2.0 nm, suggesting their potential as effective inhibitors. These findings suggest that the proposed ligands hold promise as potential scaffolds for developing potent antiviral drugs against COVID-19.
由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的全球大流行凸显了有效抗病毒疗法的迫切必要性。对病毒复制至关重要的病毒主要蛋白酶（Mpro）已成为一个有前景的治疗靶点。在本研究中，对作为母体抑制剂K36衍生物设计的十种类药物化合物（KL1-KL10）对Mpro的抑制潜力进行了计算研究。为了阐明所建议药物与Mpro活性位点的结合亲和力和相互作用，应用了分子对接和长达500纳秒的分子动力学（MD）模拟。我们的结果表明，与母体抑制剂K36相比，许多所建议的抑制剂表现出增强的结合亲和力。其中，KL7表现出最有利的结合特性，对接分数为-13.54，MM-PBSA结合能为-34.57 kJ/mol，超过了K36。分子动力学模拟表明这些化合物与Mpro持续结合，均方根偏差（RMSD）值在0.5至2.0纳米之间，表明它们作为有效抑制剂的潜力。这些发现表明，所提出的配体有望成为开发抗2019冠状病毒病（COVID-19）有效抗病毒药物的潜在支架。
