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胆固醇酯转移蛋白(cholesterol ester transfer protein,CETP)是HDL的重要调控因子,抑制其活性可有效提高HDL的含量。由于HDL通过胆固醇逆向转运对动脉粥样硬化发挥的重要遏制作用,CETP已成为治疗心血管疾病的热门靶点。该文以PDB数据库中编号为4F2A的CETP蛋白结构为研究对象,对其活性区域内的药效特征进行识别、聚类及筛选,建立了基于CETP蛋白结构的受体药效团。最优药效团由6个疏水特征、1个氢键供体特征及9个排除体积组成,其辨识有效性指数N为3.33,综合评价指数CAI为2.31。同时,利用该模型对TCMD进行虚拟筛选,获得来源于315味中药的629个化合物。最后,该研究基于分子对接技术探讨了活性区域的关键氨基酸残基以及中药活性化合物与受体的相互作用,进一步验证了研究结果的可靠性。其中枸杞子、五味子等部分含有潜在活性成分较多的中药已有文献报道确有降脂活性。该研究为从中药中发现CETP抑制剂、探讨中药降脂作用机制提供了数据支撑。
Cholesteryl ester transfer protein (CETP) is an important regulatory factor of HDL. Inhibiting its activity can effectively increase the content of HDL. CETP has become a hot target for the treatment of cardiovascular disease due to the important suppressive effect of HDL on atherosclerosis through the reverse transport of cholesterol. In this paper, the CETP protein structure of 4F2A in PDB database was taken as the research object, the pharmacophore characteristics in the active region were identified, clustered and screened, and the receptor pharmacophore based on CETP protein structure was established. The optimal pharmacophore consisted of six hydrophobic features, one hydrogen bond donor feature and nine exclusion volumes. The identification validity index N was 3.33, and the comprehensive evaluation index CAI was 2.31. At the same time, the TCMD was screened by this model and 629 compounds derived from 315 Chinese herbs were obtained. Finally, based on the molecular docking technique, the study explored the key amino acid residues in the active region and the interaction between the active compound and the receptor of the traditional Chinese medicine, further verifying the reliability of the research results. Chinese wolfberry fruit, Schisandra and other parts containing more active ingredients of traditional Chinese medicine has been reported in the literature lipid-lowering activity. This study provides data support for discovering CETP inhibitors from traditional Chinese medicine and exploring the mechanism of lipid-lowering effect of traditional Chinese medicine.