目的 開發(fā)膽固醇酯轉(zhuǎn)移蛋白（CETP）的天然產(chǎn)物抑制劑。方法 采用計(jì)算機(jī)輔助技術(shù)，對高通量篩選天然產(chǎn)物數(shù)據(jù)庫L6000分別進(jìn)行3個(gè)精度梯度的分子對接、結(jié)合自由能計(jì)算、分子動力學(xué)模擬（MD模擬）等多輪虛擬篩選的策略，從中篩選CETP抑制劑。結(jié)果 共篩選得到19個(gè)候選化合物，其中前3位化合物分別為肉蓯蓉苷A、茶黃素、丹酚酸B二甲酯，結(jié)合模式分析顯示上述化合物與靶標(biāo)活性口袋之間形成了較強(qiáng)的相互作用；MD模擬的參數(shù)也證實(shí)上述蛋白–配體復(fù)合物結(jié)合的穩(wěn)定性。結(jié)論 肉蓯蓉苷A、茶黃素、丹酚酸B二甲酯可作為CETP抑制劑的先導(dǎo)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

國家自然科學(xué)基金資助項(xiàng)目（81873060）