| 眭超亚,任小平,刘小勇,苏婷婷,刘芳,任小利,陶玲.化学通报,2026,89(4):441-448. |
| 基于生物活性评价、分子对接、分子动力学模拟发现新型hDHODH抑制剂 |
| Discovery of Novel Human Dihydroorotate Dehydrogenase Inhibitors Based on Biological Activity Evaluation, Molecular Docking, and Molecular Dynamics Simulations |
| 投稿时间：2026-01-06 修订日期：2026-02-08 |
| DOI： |
| 中文关键词: 人二氢乳清酸脱氢酶（hDHODH） 宿主靶向抗病毒药物（HTA） 体外活性测试 分子对接 分子动力学模拟 病毒 |
| 英文关键词:human dihydroorotate dehydrogenase (hDHODH) host-targeted antiviral agents (HTA) in vitro activity assay molecular docking molecular dynamics simulation virus |
| 基金项目:重庆化工职业学院科技重点项目(HZY2024-KJZD03)和重庆市教育委员会科学技术研究计划青年项目(KJQN202504505,KJQN202504509)资助 |
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| 中文摘要: |
| 近几十年来，新出现和重新出现的病毒一直是公共卫生领域的一个挑战。针对参与病毒增殖的细胞分子或途径的宿主靶向抗病毒药物（HTA）开发是一种有效策略。研究发现，人二氢乳清酸脱氢酶（human dihydroorotate dehydrogenase, hDHODH）是HTA开发的首选成药靶点。本研究报告了一类新型hDHODH抑制剂，通过体外活性测试，发现它们对hDHODH表现出较好的抑制作用，其中抑制剂5和6的IC50分别为2.66±0.06 μM和1.05±0.08 μM。分子对接研究表明，化合物5和6与hDHODH活性口袋吻合度高，且与氨基酸残基有良好的相互作用，与对照品A771726的复合物共晶结构相比，抑制剂6增加了与Leu359的直接相互作用。分子动力学模拟研究提示，与对照化合物相比，抑制剂5和6亲和力更强，且他们的复合物稳定，这也正好证实了抑制剂5和6在体外对hDHODH的显著抑制作用。本研究通过生物活性评价、分子对接、分子动力学模拟实验，发现了新型hDHODH抑制剂5和6，它们可能是一种有前途的广谱抗病毒候选药物。 |
| 英文摘要: |
| In recent decades, newly emerging and re-emerging viruses have persistently posed a challenge to the field of public health. The development of host-targeting antiviral (HTA) agents that act on cellular molecules or pathways involved in viral proliferation constitutes an effective strategy. Studies have identified human dihydroorotate dehydrogenase (hDHODH) as the preferred druggable target for HTA development. The present study reports a novel class of hDHODH inhibitors, which were found to exhibit favourable inhibitory activity against hDHODH in in vitro activity assays, with inhibitors 5 and 6 having IC50 values of 2.66±0.06 μM and 1.05±0.08 μM, respectively. Molecular docking studies revealed that compounds 5 and 6 show a high degree of compatibility with the active pocket of hDHODH and form favourable interactions with amino acid residues; in comparison with the co-crystal structure of the reference compound A771726 in complex with hDHODH, inhibitor 6 forms an additional direct interaction with Leu359. Molecular dynamics simulation studies indicated that, relative to the reference compound, inhibitors 5 and 6 possess a higher binding affinity and form stable complexes with the protein, which corroborates their significant inhibitory activity against hDHODH in vitro. Through biological activity evaluation, molecular docking and molecular dynamics simulation assays, the present study has identified novel hDHODH inhibitors 5 and 6, which represent promising broad-spectrum antiviral drug candidates. |
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