通过分子对接、体外试验、分子动力学模拟和 DFT 分析鉴定新型 SARS-CoV-2 3CLpro 抑制剂。

IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Frontiers in Pharmacology Pub Date : 2024-10-30 eCollection Date: 2024-01-01 DOI:10.3389/fphar.2024.1494953
Keli Zong, Chaochun Wei, Wei Li, Jiajun Ruan, Susu Zhang, Jingjing Li, Xiaojing Liu, Xu Zhao, Ruiyuan Cao, Hong Yan, Xingzhou Li
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引用次数: 0

摘要

引言SARS-CoV-2 大流行对全球健康和经济构成了重大威胁,因此迫切需要开发有效的抗病毒药物。SARS-CoV-2 的主要蛋白酶(3CLpro)是抗病毒治疗的关键靶点,因为它在病毒复制中起着至关重要的作用:方法:为了寻找新结构类型的 3CLpro 抑制剂,以解决新病毒耐药性问题。方法:为了寻找新结构类型的 3CLpro 抑制剂,促进解决新病毒耐药性问题,我们从包含 1000 万个化合物的 Topscience 数据库中,利用基于结构的虚拟筛选和体外检测,确定了 6 个潜在的药理生物活性化合物:其中,化合物 34 和 36 具有强效抑制活性,IC50 值分别为 6.12 ± 0.42 μM 和 4.47 ± 0.39 μM。为了阐明它们与 3CLpro 的结合机制,研究人员进行了全原子分子动力学(MD)模拟。主成分分析(PCA)、自由能图谱(FEL)和动态交叉相关图谱(DCCM)显示,化合物 34 和 36 与 3CLpro 的结合显著增强了 3CLpro 的结构稳定性,降低了构象灵活性和内部运动。蛋白质-配体相互作用的结果表明,34和36化合物与3CLpro活性位点的关键残基形成了强烈而稳定的相互作用,其结合模式与S-217622不同。HOMO-LUMO间隙和分子静电位分布揭示了34和36化合物的量子化学性质。这些发现表明,化合物 34 和 36 可作为新型 SARS-CoV-2 3CLpro 抑制剂和有希望开发 COVID-19 治疗药物的先导候选化合物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Identification of novel SARS-CoV-2 3CLpro inhibitors by molecular docking, in vitro assays, molecular dynamics simulations and DFT analyses.

Introduction: SARS-CoV-2 pandemic has presented a significant threat to global health and the economy, necessitating urgent efforts to develop effective antiviral drugs. The main protease (3CLpro) of SARS-CoV-2 is a critical target for antiviral therapy due to its essential role in viral replication.

Methods: In order to find new structural types of 3CLpro inhibitors to facilitate the solution to the problem of new virus resistance. Six potential pharmacologically bioactive compounds were identified by utilizing structure-based virtual screening and in vitro assays from the Topscience database containing 10 million compounds.

Results and discussion: Among these, compounds 34 and 36 exhibited potent inhibitory activity with IC50 values of 6.12 ± 0.42 μM and 4.47 ± 0.39 μM, respectively. To elucidate their binding mechanisms with 3CLpro, all-atom molecular dynamics (MD) simulations were conducted. Principal component analysis (PCA), free energy landscapes (FEL) and dynamic cross-correlation maps (DCCM) revealed that the binding of compounds 34 and 36 to 3CLpro significantly enhanced the structural stability of 3CLpro, reducing conformational flexibility and internal motions. The results of protein-ligand interaction showed that compounds 34 and 36 formed strong and stable interactions to key residues at active site of 3CLpro with different binding modes from S-217622. And HOMO-LUMO gap and molecular electrostatic potential distribution revealed the quantum chemical properties of compounds 34 and 36. These findings suggested that compounds 34 and 36 can be as novel SARS-CoV-2 3CLpro inhibitors and promising lead-like drug candidates for developing COVID-19 treatments.

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来源期刊
Frontiers in Pharmacology
Frontiers in Pharmacology PHARMACOLOGY & PHARMACY-
CiteScore
7.80
自引率
8.90%
发文量
5163
审稿时长
14 weeks
期刊介绍: Frontiers in Pharmacology is a leading journal in its field, publishing rigorously peer-reviewed research across disciplines, including basic and clinical pharmacology, medicinal chemistry, pharmacy and toxicology. Field Chief Editor Heike Wulff at UC Davis is supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.
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