高等学校化学学报

高等学校化学学报

• 研究论文 • 上一篇    下一篇

靶向猴痘A42R病毒的药物筛选和再利用：结合机制的模拟研究

范翔,刘子建,贾梦珂,艾洪奇   

  1. 济南大学化学化工学院
  • 收稿日期:2025-10-28 修回日期:2026-01-13 网络首发:2026-01-16 发布日期:2026-01-16
  • 通讯作者: 艾洪奇 E-mail:chm_aihq@ujn.edu.cn
  • 基金资助:
    山东省自然科学基金（批准号:ZR2022MB073）资助

Targeting Monkeypox A42R for Drug Screening and Repurposing: A Computational Study of Binding Mechanisms

FAN Xiang, LIU Zijian, JIA Mengke, AI Hongqi   

  1. School of Chemistry and Chemical Engineering, University of Jinan
  • Received:2025-10-28 Revised:2026-01-13 Online First:2026-01-16 Published:2026-01-16
  • Supported by:
    Supported by the Shandong Provincial Natural Science Foundation (No. ZR2022MB073)

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摘要： 本研究旨在通过药物再利用策略, 筛选靶向MPVX(猴痘病毒)A42R蛋白的潜在抑制剂, 以解决当前缺乏特异性抗猴痘药物的问题. 采用分子对接、分子动力学模拟与MM/PBSA(分子力学/泊松-玻尔兹曼表面积)结合自由能计算等方法, 从ZINC数据库9803个小分子中筛选出6个与A42R具有良好结合能力的候选化合物. 其中, 带两个负电荷的ZINC000000538152 结合能力最强(-236.3 kJ/mol), 其与A42R蛋白中富含精氨酸的结构域形成多个盐桥、氢键和π-阳离子相互作用, 显著增强结合稳定性. 此外, ZINC000003935130虽为中性分子, 但通过强范德华作用实现次高结合强度(-102.7 kJ/mol), 大于另外三个带一个负电荷的化合物. 结论表明, 这六个化合物都是极具潜力的、可被再利用为A42R抑制剂的候选物, 因为它们的存在阻断了A42R与肌动蛋白或PIP2(磷脂酰肌醇-4,5-二磷酸)的结合, 从而抑制病毒扩散. 本研究为MPVX药物开发提供了新思路.

关键词: MPVX, A42R 蛋白, 药物再利用, 阻断机制, 分子动力学

Abstract: The purpose of this study is to screen potential inhibitors targeting monkeypox virus A42R protein through drug reuse strategy to solve the current lack of specific anti-monkeypox drugs. 6 candidate compounds with good binding ability to A42R were screened from 9803 small molecules in the ZINC database by molecular docking, molecular dynamics simulation and MM/PBSA(Molecular Mechanics/Poisson-Boltzmann Surface Area) binding free energy calculation. Among them, ZINC000000538152 with two negative charges has the strongest binding ability (-236.3 kJ/mol). It forms multiple salt bridges, hydrogen bonds and π-cation interactions with the arginine-rich domain of the A42R protein, which significantly enhances the binding stability. In addition, although ZINC000003935130 is a neutral molecule, it achieves a sub-high binding strength (-102.7 kJ/mol) through strong van der Waals interaction, which is greater than the other three compounds with a negative charge. The conclusion shows that these six compounds are highly potential and can be reused as candidates for A42R inhibitors, because their presence blocks the binding of A42R to actin or PIP2(phosphatidylinositol-(4,5)-bisphosphate), thereby inhibiting virus spread. This study provides new ideas for the development of monkeypox virus drugs.

Key words: Monkeypox virus, A42R protein, Drug repurposing, Blocking mechanism; Molecular dynamics

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