通过虚拟筛选、分子动力学模拟和体外活性测定发现二氢乳清酸脱氢酶的新型抑制剂
Discovery of Novel Inhibitors of DHODH via Virtual Screening, MD Simulation, and In Vitro Activity Assay.
作者信息
Li Kaige, Xia Wei, Zhang John Z H
机构信息
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug, Development, Shanghai Key Laboratory of Green Chemistry & Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
NYU-ECNU Center for Computational Chemistry and Shanghai Frontiers Science Center of AI and DL, New York University Shanghai, Shanghai 200126, China.
出版信息
Molecules. 2025 Jun 16;30(12):2607. doi: 10.3390/molecules30122607.
To address the surge in infections among immunosuppressed patients and azole resistance, this study focused on developing novel inhibitors targeting dihydroorotate dehydrogenase (AfDHODH), a key enzyme in fungal pyrimidine synthesis. The three-dimensional structure of AfDHODH was constructed via homology modeling. Molecular docking, dynamics simulations, and binding free energy calculations systematically elucidated the mechanisms of existing inhibitors. Virtual screening against the ZINC20 and ChEMBL databases yielded 13 candidates, with two micromolar inhibitors (IC < 100 μM) identified through in vitro assays. These inhibitors exhibited novel scaffold structures that were distinct from known DHODH inhibitors. The results validate the feasibility of homology modeling-guided antifungal discovery and these findings provide critical insights for the development of new antifungal agents.
为应对免疫抑制患者感染激增以及唑类耐药问题，本研究聚焦于开发针对二氢乳清酸脱氢酶（AfDHODH）的新型抑制剂，该酶是真菌嘧啶合成中的关键酶。通过同源建模构建了AfDHODH的三维结构。分子对接、动力学模拟和结合自由能计算系统地阐明了现有抑制剂的作用机制。针对ZINC20和ChEMBL数据库进行虚拟筛选得到了13个候选物，通过体外试验鉴定出两种微摩尔级抑制剂（IC<100μM）。这些抑制剂展现出与已知DHODH抑制剂不同的新型支架结构。结果验证了同源建模指导抗真菌药物发现的可行性，这些发现为新型抗真菌药物的开发提供了关键见解。
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