Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou 213001, China.
Molecules. 2022 Oct 12;27(20):6823. doi: 10.3390/molecules27206823.
COVID-19 can cause different neurological symptoms in some people, including smell, inability to taste, dizziness, confusion, delirium, seizures, stroke, etc. Owing to the issue of vaccine effectiveness, update and coverage, we still need one or more diversified strategies as the backstop to manage illness. Characterizing the structural basis of ligand recognition in the main protease (M) of SARS-CoV-2 will facilitate its rational design and development of potential drug candidates with high affinity and selectivity against COVID-19. Up to date, covalent-, non-covalent inhibitors and allosteric modulators have been reported to bind to different active sites of M. In the present work, we applied the molecular dynamics (MD) simulations to systematically characterize the potential binding features of catalytic active site and allosteric binding sites in M using a dataset of 163 3D structures of M-inhibitor complexes, in which our results are consistent with the current studies. In addition, umbrella sampling (US) simulations were used to explore the dissociation processes of substrate pathway and allosteric pathway. All the information provided new insights into the protein features of M and will facilitate its rational drug design for COVID-19.
新型冠状病毒（COVID-19）可引起部分人群出现不同的神经系统症状，包括嗅觉丧失、味觉丧失、头晕、意识混乱、谵妄、癫痫发作、中风等。由于疫苗有效性、更新和覆盖率等问题，我们仍然需要一种或多种多样化的策略作为后盾来管理疾病。阐明新型冠状病毒主蛋白酶（M）中配体识别的结构基础，将有助于其合理设计和开发针对 COVID-19 的高亲和力和选择性的潜在药物候选物。迄今为止，已报道共价、非共价抑制剂和别构调节剂可结合到 M 的不同活性部位。在本工作中，我们应用分子动力学（MD）模拟，使用包含 163 个 M-抑制剂复合物三维结构的数据集，系统地研究了 M 的催化活性部位和别构结合部位的潜在结合特征。我们的结果与当前研究一致。此外，我们还使用伞状采样（US）模拟探索了底物途径和别构途径的解离过程。所有这些信息为 M 的蛋白特征提供了新的见解，并将有助于其针对 COVID-19 的合理药物设计。
