| 刘晓静,未朝春,赵旭,张凤华,李飞,李行舟.化学通报,2025,88(6):671-679. |
| 基于虚拟筛选和分子动力学模拟发现SARS-CoV-2 3CLpro抑制剂 |
| Discovery of SARS-CoV-2 3CLpro Inhibitors based on Virtual Screening and Molecular Dynamics Simulations |
| 投稿时间：2025-01-02 修订日期：2025-02-24 |
| DOI： |
| 中文关键词: COVID-19 SARS-CoV-2 3CLpro 药效团 分子对接 分子动力学模拟 |
| 英文关键词:COVID-19, SARS-CoV-2 3CLpro, pharmacophore, molecular docking, molecular dynamics simulations |
| 基金项目: |
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| 摘要点击次数: 398 |
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| 中文摘要: |
| SARS-CoV-2 3CLpro作为病毒生命周期中的关键酶,是开发新型抗病毒药物的重要靶点。本研究通过Schr?dinger 2024-1软件的Phase模块,构建了SARS-CoV-2 3CLpro抑制剂的药效团模型。基于此药效团模型,对ZINC20数据库中的1030万个小分子进行了初步虚拟筛选,筛选出25689个符合药效团特征的小分子,并进一步通过分子对接和MM/GBSA计算筛选出5个优质候选化合物。200 ns的分子动力学模拟表明,这些化合物在稳定性和构象分布上表现优异,FEL分析显示其具有较高的动态稳定性。蛋白配体相互作用分析揭示,候选化合物与3CLpro形成多种非共价相互作用,增强了结合稳定性。结合自由能计算结果表明,候选化合物的结合自由能优于参考化合物显示出最佳结合亲和力和稳定性。综上所述,本研究为SARS-CoV-2 3CLpro抑制剂的设计提供了重要理论依据和候选分子。 |
| 英文摘要: |
| SARS-CoV-2 3CL protease is a key enzyme in the viral life cycle and an important target for the development of novel antiviral drugs. In this study, the Phase module of Schr?dinger 2024-1 software was used to construct a pharmacophore model for SARS-CoV-2 3CL protease inhibitors. Based on this pharmacophore model, an initial virtual screening was conducted on 10.3 million small molecules from the ZINC20 database, identifying 25,689 compounds that matched pharmacophore features. These compounds were further screened through molecular docking and MM/GBSA calculations, resulting in the identification of five promising candidate inhibitors. A 200 ns molecular dynamics simulation revealed that these compounds exhibited excellent stability and favorable conformational distribution, with free energy landscape (FEL) analysis indicating higher dynamic stability. Protein-ligand interaction analysis showed that the candidates formed various non-covalent interactions with the 3CL protease, enhancing binding stability. Binding free energy calculations indicated that the candidate compounds exhibited better binding affinity and stability than the reference compound. In conclusion, this study provides important theoretical insights and candidate molecules for the design of SARS-CoV-2 3CL protease inhibitors. |
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