Coronavirus-2 Main protease (SARS-CoV-2 M^pro), one of the most vital enzymes of the new coronavirus-2 (SARS-CoV-2) and a crucial target for drug discovery, has been battered with numerous types of drugs/inhibitors. Regrettably, till date there is no any potential drugs or effective inhibitors available to combat its action. Based on the reports of HIV-protease inhibitors can be applied against the SARS by targeting the SARS-CoV-1 M^pro, we have chosen few clinically trialed experimental HIV-protease inhibitors (JE-2147, KNI-227 and KNI-272) and a variant JE2-CH3, to examine their binding affinities with SARS-CoV-2 M^pro and to assess their potential to check for a possible drug candidate against the protease. Here, we have chosen a methodology to understand the rational elucidation of the binding mechanism of these four inhibitors to SARS-CoV-2 M^pro by merging molecular docking, Molecular Dynamics (MD) simulation, and MM-PBSA based free energy calculations. Our estimations disclose that JE-2147 is highly effective (-14.95 kcal/mol) compared to JE2-CH3 (--11.19 kcal/mol), KNI-227 (-13.93 kcal/mol) and KNI-272 (-12.84 kcal/mol) against SARS-CoV-2 M^pro. The increase in binding affinity for JE-2147 comparative to other three inhibitors arises due to an increased favorable van der Waals interactions and decreased solvation energies between the inhibitor and viral protease. Residue decomposition analysis and hydrogen bonding pattern confirms binding affinities of the inhibitors crucial for the interactions. Binding contributions of important residues (His41, Met49, Cys145, His164, Met165, Pro168, Gln189 etc.) from the active site or near the active site regions with more than 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^pro drugs.


中文翻译：

---

含SARS-CoV-2 Mpro的HIV蛋白酶抑制剂的异苯基降他汀的药物再利用：分子动力学模拟和结合自由能估计的见解

冠状病毒2主要蛋白酶（SARS-CoV-2 M ^pro）是新型冠状病毒2（SARS-CoV-2）最重要的酶之一，也是药物发现的关键靶标，已被多种药物所困扰/抑制剂。令人遗憾的是，迄今为止，尚没有任何潜在的药物或有效的抑制剂可用于对抗其作用。根据HIV蛋白酶抑制剂可通过靶向SARS-CoV-1 M ^pro来抗击SARS的报道，我们选择了几项经过临床试验的实验性HIV蛋白酶抑制剂（JE-2147，KNI-227和KNI-272）和一个变体JE2-CH3，以检查它们与SARS-CoV-2 M ^pro的结合亲和力并评估其针对蛋白酶检查可能的候选药物的潜力。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的自由能计算来理解这四种抑制剂与SARS-CoV-2 M ^pro结合机理的合理解释。我们的估算表明，与JE2-CH3（--11.19 kcal / mol），KNI-227（-13.93 kcal / mol）和KNI-272（-12.84 kcal / mol）相比，JE-2147的高效性（-14.95 kcal / mol）摩尔）对SARS-CoV-2 M ^pro。与其他三种抑制剂相比，对JE-2147的结合亲和力增加是由于抑制剂与病毒蛋白酶之间有利的范德华相互作用增加和溶剂化能降低所致。残留物分解分析和氢键合模式证实了对于相互作用至关重要的抑制剂的结合亲和力。来自活性位点或活性位点附近区域的重要残基（His41，Met49，Cys145，His164，Met165，Pro168，Gln189等）的结合贡献具有大于1.0 kcal / mol的抑制力。可以预期，目前对这些含APNS抑制剂的结合相互作用的研究可以提供一些有价值的见识，以设计出显着有效的抗SARS-CoV-2 M^前体药物。