Division of Infectious Diseases and Division of Computer Aided Drug Design, The Red-Green Research Centre, BICCB, Tejgaon, Dhaka, Bangladesh.
Key Laboratory of Soft Chemistry and Functional Materials of MOE, School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, China.
J Biomol Struct Dyn. 2022 Mar;40(4):1639-1658. doi: 10.1080/07391102.2020.1831610. Epub 2020 Oct 13.
In viral replication and transcription, the main protease (Mpro) of SARS-CoV-2 plays an important role and appears to be a vital target for drug design. In Mpro, there is a Cys-His catalytic dyad, and ligands that interact with the Cys145 assumed to be an effective approach to inhibit the Mpro. In this study, approximately 1400 cysteine-focused ligands were screened to identify the best candidates that can act as potent inhibitors against Mpro. Our results show that the selected ligands strongly interact with the key Cys145 and His41 residues. Covalent docking was performed for the selected candidates containing the acrylonitrile group, which can form a covalent bond with Cys145. All atoms molecular dynamics (MD) simulation was performed on the selected four inhibitors including L1, L2, L3 and L4 to validate the docking interactions. Our results were also compared with a control ligand, α-ketoamide (11r). Principal component analysis on structural and energy data obtained from the MD trajectories shows that L1, L3, L4 and α-ketoamide (11r) have structural similarity with the apo-form of the Mpro. Quantitative structure-activity relationship method was employed for pattern recognition of the best ligands, which discloses that ligands containing acrylonitrile and amide warheads can show better performance. ADMET analysis displays that our selected candidates appear to be safer inhibitors. Our combined studies suggest that the best cysteine focused ligands can help to design an effective lead drug for COVID-19 treatment. Communicated by Ramaswamy H. Sarma.
在病毒复制和转录过程中，SARS-CoV-2 的主要蛋白酶（Mpro）发挥着重要作用，似乎是药物设计的重要靶点。在 Mpro 中，存在一个 Cys-His 催化二联体，与假定能有效抑制 Mpro 的 Cys145 相互作用的配体。在这项研究中，筛选了大约 1400 种针对半胱氨酸的配体，以确定可作为针对 Mpro 的有效抑制剂的最佳候选物。我们的研究结果表明，所选配体与关键的 Cys145 和 His41 残基强烈相互作用。对含有丙烯腈基团的选定候选物进行了共价对接，该基团可以与 Cys145 形成共价键。对包括 L1、L2、L3 和 L4 在内的选定的四种抑制剂进行了所有原子分子动力学（MD）模拟，以验证对接相互作用。我们的结果还与对照配体 α-酮酰胺（11r）进行了比较。从 MD 轨迹获得的结构和能量数据的主成分分析表明，L1、L3、L4 和 α-酮酰胺（11r）与 Mpro 的无配体形式具有结构相似性。采用定量构效关系方法对最佳配体进行模式识别，结果表明含有丙烯腈和酰胺弹头的配体具有更好的性能。ADMET 分析显示，我们选择的候选物可能是更安全的抑制剂。我们的综合研究表明，最佳的半胱氨酸聚焦配体可以帮助设计针对 COVID-19 治疗的有效先导药物。Ramaswamy H. Sarma 通讯。
