胆固醇酯转运蛋白抑制剂的分子设计  

Designing novel inhibitors by targeting cholesteryl ester transfer protein

作　　者：刘炳旺[1,2] 马英[1] 李彬寒 王润玲[1] 

机构地区：[1]天津医科大学药学院,天津市临床药物关键技术重点实验室,天津300070 [2]天津医科大学肿瘤医院分子影像及核医学诊疗科,国家肿瘤临床医学研究中心,天津市"肿瘤防治"重点实验室,天津300060

出　　处：《天津医科大学学报》2016年第2期122-125,共4页Journal of Tianjin Medical University

摘　　要：目的:设计针对胆固醇酯转运蛋白(CETP)的抑制剂,提高其降低血脂水平,为以后相关疾病的治疗提供科学的方法和依据。方法:以现有torcetrapib抑制剂为模板,利用Schrodinger Suite 2009软件中的"Core Hopping"模块进行修饰,对修饰后的结构用"Core Hopping"模块改造结构;利用Schrodinger Suite2009中的Glide模块对druglike数据库中10万个化合物进行高通量虚拟筛选,得到结构进行修饰。利用Glide模块对所建立的化合物库进行虚拟筛选。应用Qikprop模块做ADME(吸收、分布、代谢、排泄)预测来推测这些化合物的成药可能性。结果:对torcetrapib结构进行修饰,得到8个较好的化合物;通过对druglike数据库进行高通量虚拟筛选得到1个化合物-ZINC26608950,修饰后得到6个化合物。用分子对接方法分析了新抑制剂和CETP的相互作用机制,与现有的抑制剂torcetrapib相比有更好的结合能力。通过ADME预测得出设计出的化合物均符合类药5原则。结论:通过两种方法得到14个CETP抑制剂,分子对接初步证明其可以抑制CETP,此为CETP抑制剂的结构改造及活性测定奠定了基础。Objective： To develop highly active cholesteryl ester transfer protein（CETP）novel inhibitors to facilitate further research.Methods： In this study, torcetrapib was modified by means of ＂core hopping＂; the small molecule drug-like database was screened by Glide of Schrodinger Suite 2009 and then was modified. It was further validated by the outcomes of their ADME（absorption, distribution,metabolism, and excretion） predictions that the new agonists could have high potential tObecome drug candidates. Results：Eight compounds were discovered to inhibit CETP based on torcetrapib by means of ＂core hopping＂. One CETP inhibitor- ZINC26608950 was discovered by high throughput virtual screening, and 6 compounds were discovered to inhibit CETP based on ZINC26608950. It was observed by docking that these novel inhibitors had more favorable conformation for binding to the receptor than torcetrapib. It was predicted that the values for these novel candidates were all within the reasonable ranges. Conclusion： The binding affinity of the designed molecules is theoretically higher than the torcetrapib in CETP. And the new inhibitors may become potential drug hits.

关 键 词：胆固醇酯转运蛋白 抑制剂 药物设计 分子对接 

分 类 号：R914.2[医药卫生—药物化学]