胆固醇酯转移蛋白天然产物抑制剂虚拟筛选和分子动力学模拟验证  

Virtual screening and molecular dynamics simulation verification of cholesterol ester transfer protein from natural product inhibitors

作　　者：缪晓帆[1] 李碧霞 尚文斌[2,3] MIAO Xiaofan;LI Bixia;SHANG Wenbin(Department of Cardiology,The Affiliated Hospital of Nanjing University of Tradition Chinese Medicine,Nanjing 210029,China;Key Laboratory for Metabolic Diseases in Chinese Medicine,First College of Clinical Medicine,Nanjing University of Chinese Medicine,Nanjing 210023,China;Department of Endocrinology and Metabolism,Affiliated Hospital of Nanjing University of Chinese Medicine,Nanjing 210029,China)

机构地区：[1]南京中医药大学附属医院心内科,江苏南京210029 [2]南京中医药大学第一临床医学院代谢病中医研究重点实验室,江苏南京210023 [3]南京中医药大学附属医院内分泌科,江苏南京210029

出　　处：《现代药物与临床》2024年第12期3021-3028,共8页Drugs & Clinic

基　　金：国家自然科学基金资助项目(81873060)。

摘　　要：目的开发胆固醇酯转移蛋白(CETP)的天然产物抑制剂。方法采用计算机辅助技术,对高通量筛选天然产物数据库L6000分别进行3个精度梯度的分子对接、结合自由能计算、分子动力学模拟(MD模拟)等多轮虚拟筛选的策略,从中筛选CETP抑制剂。结果共筛选得到19个候选化合物,其中前3位化合物分别为肉苁蓉苷A、茶黄素、丹酚酸B二甲酯,结合模式分析显示上述化合物与靶标活性口袋之间形成了较强的相互作用;MD模拟的参数也证实上述蛋白-配体复合物结合的稳定性。结论肉苁蓉苷A、茶黄素、丹酚酸B二甲酯可作为CETP抑制剂的先导化合物。Objective To develop natural product inhibitors of cholesterol ester transfer protein(CETP).Methods By using computer-aided technology,the high-throughput natural product database L6000 was screened for CETP inhibitors by multi-round virtual screening strategies such as molecular docking with three precision gradients,combined free energy calculation and molecular dynamics simulation(MD simulation).Results A total of 19 candidate compounds were screened,of which the first three compounds were cistanosideA,theaflavin and dimethyllithospermate B.Binding mode analysis showed that there was a strong interaction between the above compounds and the active pocket of the target,and the MD simulation parameters also confirmed the stability of the protein-ligand complex mentioned above.Conclution CistanosideA,theaflavin,and dimethyllithospermate B can be used as the lead compounds of possible CETP inhibitors.

关 键 词：开发胆固醇酯转移蛋白 血脂异常 天然化合物 小分子抑制剂 虚拟筛选 分子对接 分子动力学模拟 肉苁蓉苷A 茶黄素 丹酚酸B二甲酯 

分 类 号：R972[医药卫生—药品]