HMG-CoA还原酶的活性位点分析及其抑制剂药效团模型的构建

Active site analysis and pharmacophore model for HMGR inhibitors

HMG-CoA还原酶(HMG-CoA Reductase,HMGR)是降血脂药物设计的重要靶标,抑制该酶的活性可以有效地降低血浆总胆固醇水平,从而降低心脑血管疾病的发病几率。虽然已经开发了数种他汀类药物作为HMGR抑制剂应用于临床,但是他汀类药物的安全性,特别是长期服用的安全性一直备受关注,所以设计新型安全的HMGR抑制剂仍然十分迫切。本论文利用蛋白质活性位点分析程序Grid,分析了HMGR底物结合腔的形状和表面特性,在细致地分析了各类药物与HMGR具体的氢键、疏水相互作用后,结合分子对接、3D-QSAR研究结果,总结了HMGR抑制剂的药效基团模型,并提出了可行的HMGR抑制剂的设计方案,为全新HMGR抑制剂的设计和先导化合物的优化提供了可靠的信息,并对HMGR抑制剂的进一步修饰提出了可行的思路。

Elevated concentration of plasma cholesterol is a major risk factor for the development of coronary heart disease. 3-hydroxy-3-methyl-glutaryl-CoA reductase（HMGR）,the natural target and the rate-limiting enzyme in cholesterol biosynthetic pathway,was an attractive target for plasma cholesterol concentration reducing drugs.In this paper,active site analysis method was employed to explore the protein active cavity＇s shape and surface properties.Based on carefully analysis of protein-inhibitors interaction,also the results of active site analysis,molecular docking and 3D-QSAR,the pharmacophore of HMGR inhibitors were identified.Possible approaches for HMGR inhibitor design/optimization were proposed.