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 RORγReverse Agonists

作　　者：吴伟俊 吴峥[1,2] 李梦婷 Wu Weijun;Wu Zheng;Li Mengting(School of Pharmaceutical Science,Guangxi Medical University,Nanning,530021;Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation,Guangxi Medical University,Nanning,530021)

机构地区：[1]广西医科大学药学院,南宁530021 [2]广西医科大学广西生物活性分子研究与评价重点实验室,南宁530021

出　　处：《化学通报(中英文)》2025年第3期335-343,共9页Chemistry

基　　金：国家大学生创新创业训练计划项目(202010598035);国家自然科学基金项目(82260671)资助。

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,r^(2)=0.990,r^(2)_(pred)=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。Retinoic acid receptor-related orphan receptorγ(RORγ)plays an important role in proliferation,survival and migration of castration-resistant prostate cancer(CRPC)cells.Recent research has demonstrated the potential of RORγreverse agonist in effectively addressing CRPC resistance,thus indicating promising prospects for development.In this study,a 3D-QSAR model of RORγreverse agonist was developed using Topomer CoMFA technology,demonstrating excellent predictive performance(q2=0.934,r^(2)=0.990,r^(2)_(pred)=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 RORγinverse 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 RORγprotein(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.

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 

分 类 号：R73[医药卫生—肿瘤]