| 吴伟俊,吴峥,李梦婷.化学通报,2025,88(3):335-343. |
| 2-苯基苯并咪唑类RORγ反向激动剂的3D-QSAR、分子对接和分子动力学研究 |
| Study on 3D-QSAR, molecular docking and molecular dynamics of 2-phenylbenzimidazole RORγ reverse agonists |
| 投稿时间：2024-11-03 修订日期：2024-11-21 |
| DOI： |
| 中文关键词: 2-苯基苯并咪唑类衍生物，去势抵抗性前列腺癌，3D-QSAR，虚拟筛选，分子对接，分子动力学，ADMET |
| 英文关键词:2-phenylbenzimidazole derivatives,CRPC,3D-QSAR,Virtual screening,Molecular docking,Molecular dynamics,ADMET |
| 基金项目:国家自然科学基金项目(82260671)和国家大学生创新创业训练计划项目(202010598035)资助 |
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| 中文摘要: |
| 维甲酸受体相关孤儿受体γ（RORγ）在去势抵抗性前列腺癌（CRPC）细胞增殖、存活和迁移中起重要作用。研究表明RORγ反向激动剂能有效地克服CRPC耐药，极具开发前景。本文基于Topomer CoMFA技术构建了预测能力较优的RORγ反向激动剂3D-QSAR模型（q2=0.934，r2=0.990，r2pred=0.986），在此基础上应用Topomer Search技术对472,316个类药化合物开展虚拟筛选，获得了5个预测活性和Total Score均优于文献的新型2-苯基苯并咪唑RORγ反向激动剂衍生物。然后，挑选Total Score得分最高的化合物D02进行分子动力学研究，结果表明化合物D02能够与RORγ蛋白（PDB ID: 6J1L）上的关键氨基酸残基稳定结合。ADMET预测结果表明，经过虚拟筛选所获得的5个化合物均具有较好的生物利用度，血脑屏障透过率低，低毒且易合成，具备进一步开发为先导化合物的潜力。 |
| 英文摘要: |
| Retinoic acid receptor-related orphan receptor γ (RORγ) plays an important role in proliferation, survival and migration of castration-resistant prostate cancer (CRPC) cells. Recent research has demonstrated the potential of RORγ reverse agonist in effectively addressing CRPC resistance, thus indicating promising prospects for development. In this study, a 3D-QSAR model of RORγ reverse agonist was developed using Topomer CoMFA technology, demonstrating excellent predictive performance (q2=0.934, r2=0.990, r2pred=0.986). Based on this model, Topomer Search technology was utilized to perform virtual screening of 472,316 drug compounds, resulting in the identification of 5 novel 2-phenylbenzimidazole RORγ inverse agonist derivatives with superior predictive activity and Total Score compared to those reported in the literature. Subsequently, compound D02 with the highest Total Score was chosen for molecular dynamics investigation, revealing its ability to form stable binding to key amino acid residues on RORγ protein (PDB ID: 6J1L). The ADMET prediction results indicated that, 5 compounds identified through virtual screening exhibited favorable bioavailability, low blood-brain barrier permeability, minimal toxicity, and facile synthesis. These findings suggest their potential for further development as lead compounds. |
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