Virtual Screening and Molecular Dynamics Simulation Targeting the ATP Domain of African Swine Fever Virus Type II DNA Topoisomerase

文献类型： 外文期刊

第一作者： Zhao, Rui

作者： Zhao, Rui;Zhao, Dongming;Zhao, Rui;Tesfagaber, Weldu;Song, Linfei;Zhang, Zhenjiang;Li, Fang;Bu, Zhigao;Zhao, Dongming;Hou, Lezi

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关键词： ASFV; type II DNA topoisomerase; ATPase domain; small molecule inhibitors; virtual screening

期刊名称：VIRUSES-BASEL （ 影响因子：3.5； 五年影响因子：3.7 ）

ISSN：

年卷期： 2025 年 17 卷 5 期

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收录情况： SCI

摘要： African Swine Fever Virus (ASFV) Topo II ATPase domain, resistant to conventional inhibitors (e.g., ICRF-187) due to M18/W19 steric clashes, was targeted via hierarchical virtual screening (Schr & ouml;dinger) of the Chembridge library combined with MM/GBSA calculations. Five ligands (10012949, 40242484, 46712145, 15880207, and 33688815) showed high affinity, with 46712145 adopting symmetrical pi-pi stacking, hydrogen bonds, and alkyl interactions to bypass steric hindrance. Molecular dynamics simulations (100 ns) revealed ligand-induced flexibility, evidenced by elevated RMSD/Rg values versus the free protein. DCCM analysis highlighted enhanced anti-correlated motions between GHKL motifs and sensor domains in chain B/C, suggesting stabilization of a non-catalytic conformation to inhibit ATP hydrolysis. Free energy landscape (FEL) analysis showed 46712145 occupying a broad, shallow energy basin, enabling conformational adaptability, contrasting the narrow deep well of the free protein. This study proposes a symmetric ligand design strategy and conformational capture mechanism to block ATPase activity. Compound 46712145 demonstrates stable binding and dynamic regulation, providing a novel lead scaffold for anti-ASFV drug development. These findings establish a structural framework for combating ASFV through targeted ATPase inhibition.

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