Zong Keli, Wei Chaochun, Li Wei, Wang Cong, Ruan Jiajun, Liu Xiaojing, Zhang Susu, Yan Hong, Cao Ruiyuan, Li Xingzhou
College of Chemistry and Life Science, Beijing University of Technology, Beijing, P.R. China.
Beijing Institute of Pharmacology and Toxicology, Beijing, P.R. China.
J Enzyme Inhib Med Chem. 2025 Dec;40(1):2463006. doi: 10.1080/14756366.2025.2463006. Epub 2025 Feb 12.
The DENV-NS5 RNA-dependent RNA polymerase (RdRp) is essential for viral replication, and one of the targets of anti-virus. In this study, the Uni-VSW module was used to virtual screen 1.6 million compounds in the ChemDiv and TargetMol (USA) database, 27 candidates were obtained. Thereby 23 candidates were selected based on their binding free energies by 50 ns MD simulations. The biological activity of the candidates and the reference compounds ( and ) were evaluated on their IC values against DENV-NGC, CC values, and selectivity index. Among these, the IC values of and were 13.06 ± 1.17 μM and 14.79 ± 7.76 μM, respectively, which were better than that of (IC =19.67 ± 1.12 μM). The comprehensive MD simulations were performed on the candidates to assess the stability behaviour and binding mechanisms. The density functional theory (DFT) analysis was also conducted to explore the structural and electronic properties.
登革病毒非结构蛋白5（DENV-NS5）的RNA依赖性RNA聚合酶（RdRp）对病毒复制至关重要，是抗病毒的靶点之一。在本研究中，利用Uni-VSW模块对ChemDiv和美国TargetMol数据库中的160万种化合物进行虚拟筛选，获得了27个候选化合物。通过50纳秒的分子动力学（MD）模拟，根据结合自由能从中筛选出23个候选化合物。对候选化合物和参考化合物（及）针对登革病毒新几内亚C株（DENV-NGC）的半数抑制浓度（IC）值、细胞毒性浓度（CC）值和选择性指数进行了生物活性评估。其中，和的IC值分别为13.06±1.17微摩尔和14.79±7.76微摩尔，优于（IC=19.67±1.12微摩尔）。对候选化合物进行了全面的分子动力学模拟，以评估其稳定性行为和结合机制。还进行了密度泛函理论（DFT）分析，以探究其结构和电子性质。
