Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Berhampur, Odisha, 760010, India.
Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Berhampur, Odisha, 760010, India.
Comput Biol Med. 2022 Mar;142:105183. doi: 10.1016/j.compbiomed.2021.105183. Epub 2021 Dec 29.
With numerous infections and fatalities, COVID-19 has wreaked havoc around the globe. The main protease (Mpro), which cleaves the polyprotein to form non-structural proteins, thereby helping in the replication of SARS-CoV-2, appears as an attractive target for antiviral therapeutics. As FDA-approved drugs have shown effectiveness in targeting Mpro in previous SARS-CoV(s), molecular docking and virtual screening of existing antiviral, antimalarial, and protease inhibitor drugs were carried out against SARS-CoV-2 Mpro. Among 53 shortlisted drugs with binding energies lower than that of the crystal-bound inhibitor α-ketoamide 13 b (-6.7 kcal/mol), velpatasvir, glecaprevir, grazoprevir, baloxavir marboxil, danoprevir, nelfinavir, and indinavir (-9.1 to -7.5 kcal/mol) were the most significant on the list (hereafter referred to as the 53-list). Molecular dynamics (MD) simulations confirmed the stability of their Mpro complexes, with the MMPBSA binding free energy (ΔG) ranging between -124 kJ/mol (glecaprevir) and -28.2 kJ/mol (velpatasvir). Despite having the lowest initial binding energy, velpatasvir exhibited the highest ΔG value for escaping the catalytic site during the MD simulations, indicating its reduced efficacy, as observed experimentally. Available inhibition assay data adequately substantiated the computational forecast. Glecaprevir and nelfinavir (ΔG = -95.4 kJ/mol) appear to be the most effective antiviral drugs against Mpro. Furthermore, the remaining FDA drugs on the 53-list can be worth considering, since some have already demonstrated antiviral activity against SARS-CoV-2. Hence, theoretical pK (K = inhibitor constant) values for all 53 drugs were provided. Notably, ΔG directly correlates with the average distance of the drugs from the His41-Cys145 catalytic dyad of Mpro, providing a roadmap for rapid screening and improving the inhibitor design against SARS-CoV-2 Mpro.
由于 COVID-19 感染和死亡人数众多，它在全球范围内造成了严重破坏。主蛋白酶（Mpro）可将多蛋白切割成非结构蛋白，从而有助于 SARS-CoV-2 的复制，因此它是抗病毒治疗的一个有吸引力的靶点。由于 FDA 批准的药物在以前的 SARS-CoV(s) 中针对 Mpro 显示出了有效性，因此对现有的抗病毒、抗疟和蛋白酶抑制剂药物进行了针对 SARS-CoV-2 Mpro 的分子对接和虚拟筛选。在结合能低于晶体结合抑制剂 α-酮酰胺 13b（-6.7 kcal/mol）的 53 种候选药物中，velpatasvir、glecaprevir、grazoprevir、baloxavir marboxil、danoprevir、nelfinavir 和 indinavir（-9.1 至-7.5 kcal/mol）在列表中最为显著（以下简称 53 列表）。分子动力学（MD）模拟证实了它们的 Mpro 复合物的稳定性，MMPBSA 结合自由能（ΔG）范围在-124 kJ/mol（glecaprevir）和-28.2 kJ/mol（velpatasvir）之间。尽管 velpatasvir 的初始结合能最低，但在 MD 模拟中它逃离催化位点的ΔG 值最高，表明其疗效降低，这与实验观察结果一致。现有的抑制测定数据充分证实了计算预测。glecaprevir 和 nelfinavir（ΔG =-95.4 kJ/mol）似乎是针对 Mpro 的最有效的抗病毒药物。此外，53 列表中剩余的 FDA 药物也值得考虑，因为其中一些药物已经证明对 SARS-CoV-2 具有抗病毒活性。因此，为所有 53 种药物提供了理论 pK（K=抑制剂常数）值。值得注意的是，ΔG 与药物与 Mpro 的 His41-Cys145 催化二联体的平均距离直接相关，为快速筛选和改进针对 SARS-CoV-2 Mpro 的抑制剂设计提供了路线图。
