论文标题
通过基于结构的配体设计和分子建模抑制冠状病毒19的主要蛋白酶3Cl-Pro
Inhibition of the Main Protease 3CL-pro of the Coronavirus Disease 19 via Structure-Based Ligand Design and Molecular Modeling
论文作者
论文摘要
我们采用了一种基于虚拟筛选，对接和分子动力学技术的协同作用的计算策略，旨在鉴定对SARS-COV2冠状病毒主要蛋白酶3Cl-Pro的非共价抑制可能的铅化合物。基于最近分辨的6LU7 PDB结构，使用基于多模式结构的设计生成配体，然后最佳地扩展到6LU7单体。对接计算表明，在SARS-COV和SARS-COV2的主要蛋白酶中，配体结合在催化性Cys-His-His-His-dyad的质子化状态下，非常相似。发现最有效的对接配体与伪线性布置中的可旋转键相连的芳香族部分共享共同的结合模式。分子动力学计算完全证实了通过对接识别的最有效粘合剂的3Cl-Pro结合袋中的稳定性，即氯苯基吡啶基 - 羧酰胺衍生物。
We have applied a computational strategy, based on the synergy of virtual screening, docking and molecular dynamics techniques, aimed at identifying possible lead compounds for the non-covalent inhibition of the main protease 3CL-pro of the SARS-Cov2 Coronavirus. Based on the recently resolved 6LU7 PDB structure, ligands were generated using a multimodal structure-based design and then optimally docked to the 6LU7 monomer. Docking calculations show that ligand-binding is strikingly similar in SARS-CoV and SARS-CoV2 main proteases, irrespectively of the protonation state of the catalytic CYS-HIS dyad. The most potent docked ligands are found to share a common binding pattern with aromatic moieties connected by rotatable bonds in a pseudo-linear arrangement. Molecular dynamics calculations fully confirm the stability in the 3CL-pro binding pocket of the most potent binder identified by docking, namely a chlorophenyl-pyridyl-carboxamide derivative.
