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.

R972

国家自然科学基金资助项目（81873060）