Computational Biology and Bioinformatics Laboratory, PG Department of Botany, Berhampur University, Berhampur, India.
Department of Chemistry, Hanyang University, Seoul, South Korea.
J Biomol Struct Dyn. 2023 Jun;41(9):3900-3913. doi: 10.1080/07391102.2022.2059008. Epub 2022 Apr 7.
SARS-CoV-2 M is one of the most vital enzymes of the new coronavirus-2 (SARS-CoV-2) and is a crucial target for drug discovery. Unfortunately, there is not any potential drugs available to combat the action of SARS-CoV-2 M. Based on the reports HIV-protease inhibitors can be applied against the SARS by targeting the SARS-CoV-1 M, we have chosen few clinically trialed experimental and allophenylnorstatine (APNS) containing HIV-protease inhibitors (JE-2147, JE-533, KNI-227, KNI-272 & KNI-1931), to examine their binding affinities with SARS-CoV-2 M and to assess their potential to check for a possible drug candidate against the protease. Here, we have chosen a methodology to understand the binding mechanism of these five inhibitors to SARS-CoV-2 M by merging molecular docking, molecular dynamics (MD) simulation and MM-PBSA based free energy calculations. Our estimations disclose that JE-2147 is highly effective (Δ = -28.31 kcal/mol) due to an increased favorable van der Waals (Δ) interactions and decreased solvation (Δ) energies between the inhibitor and viral protease. JE-2147 shows a higher level of interactions as compared to JE-533 (-6.85 kcal/mol), KNI-227 (-18.36 kcal/mol), KNI-272 (-15.69 kcal/mol) and KNI-1931 (-21.59 kcal/mol) against SARS-CoV-2 M. Binding contributions of important residues (His41, Met49, Cys145, His164, Met165, Glu166, Pro168, Gln189, etc.) from the active site or near the active site regions with ≥1.0 kcal/mol suggest a potent binding of the inhibitors. It is anticipated that the current study of binding interactions of these APNS containing inhibitors can pitch some valuable insights to design the significantly effective anti-SARS-CoV-2 M drugs.Communicated by Ramaswamy H. Sarma.
SARS-CoV-2 M 是新型冠状病毒-2（SARS-CoV-2）中最重要的酶之一，也是药物发现的关键靶标。不幸的是，目前还没有针对 SARS-CoV-2 M 的潜在药物。基于报道称 HIV 蛋白酶抑制剂可以通过针对 SARS-CoV-1 M 来对抗 SARS，我们选择了一些经过临床试验的实验性和全苯异丝氨酸（APNS）含 HIV 蛋白酶抑制剂（JE-2147、JE-533、KNI-227、KNI-272 和 KNI-1931），以检查它们与 SARS-CoV-2 M 的结合亲和力，并评估它们作为蛋白酶潜在药物候选物的潜力。在这里，我们选择了一种方法，通过合并分子对接、分子动力学（MD）模拟和基于 MM-PBSA 的自由能计算来了解这五种抑制剂与 SARS-CoV-2 M 的结合机制。我们的估计表明，JE-2147 非常有效（Δ=-28.31 kcal/mol），因为抑制剂与病毒蛋白酶之间增加了有利的范德华（Δ）相互作用和减少了溶剂化（Δ）能量。JE-2147 与 SARS-CoV-2 M 的相互作用水平高于 JE-533（-6.85 kcal/mol）、KNI-227（-18.36 kcal/mol）、KNI-272（-15.69 kcal/mol）和 KNI-1931（-21.59 kcal/mol）。来自活性位点或靠近活性位点区域的重要残基（His41、Met49、Cys145、His164、Met165、Glu166、Pro168、Gln189 等）的结合贡献≥1.0 kcal/mol 表明抑制剂具有很强的结合能力。预计，目前对这些含有 APNS 的抑制剂结合相互作用的研究可以为设计有效的抗 SARS-CoV-2 M 药物提供一些有价值的见解。由 Ramaswamy H. Sarma 传达。
