胆固醇酯转运蛋白抑制剂的对接和分子模拟研究

发布时间：2018-03-23 09:45

本文选题：对接机制　切入点：胆固醇转运蛋白抑制剂　出处：《天津大学》2012年硕士论文　论文类型：学位论文

【摘要】：胆固醇酯转运蛋白(Cholesteryl Ester Transfer Protein, CETP)是一种血浆糖蛋白，它介导胆固醇酯(Cholesteryl Ester, CE)从高密度脂蛋白(High-density Lipoproteins, HDL)转运到低密度脂蛋白(Low-densityLipoproteins, LDL)和极低密度脂蛋白(Very Low-density Lipoproteins,VLDL)，同时将等量的甘油三酯(Triglyceride, TG)分子反向转运。CETP的转运过程会降低有抗动脉硬化作用的HDL的血液浓度，并提高有致动脉硬化作用的LDL和VLDL的血液浓度。因此，抑制CETP介导的转运过程将成为一种治疗心血管疾病的好方法。实验以曾经报道过活性较高且有代表性的41个CETP抑制剂分子为研究目标，，采用Dock6.2软件，取复合物中原配体周围10范围为活性位点对这41个化合物进行分子对接。根据对接的结果，验证了抑制剂本身的生物活性与CETP对接结果是基本一致的，并初步确定了抑制剂与受体相互作用的潜在结合位点。通过Dock对接研究，筛选出打分值和活性值最好的一类N,N-双取代的三氟-3-氨基-2-丙醇类CETP抑制剂化合物。为了深入的调查研究这些抑制剂化合物对接过程中的作用位点和作用机制，我们利用AutoDock软件完成了更细致的分子对接工作，成功的确认了有效的活性位点。此外，为确保对接结果的科学性和准确性，我们借助Amber软件进行了一系列的分子动力学模拟运算(MolecularDynamics, MD)。对接结果显示抑制剂与受体CETP作用的活性区域主要分布在两个疏水区域（P1和P2），这两个活性位点可以有效地结合化合物的亲脂性侧链或基团，进行有效的相互作用。通过实验，P1的Val421和P2的Met194氨基酸残基在构成疏水区域上起着关键作用。在P2区域的氨基酸残基Phe197和Phe463和配体分子有着π-π双键共轭的作用。其它取代基比如：3-苯氧基上的疏水取代基同样促进抑制作用，3-位的四氟乙氧基苯基引起的疏水性会优于一个较短的取代基所带来的作用。受体CETP和配体抑制剂小分子的作用机制能够成功的解释为什么不同的抑制剂结构会有着不同的抑制活性。我们期待这些发现能够为CETP相关的心脑血管疾病提供有益的信息和指导，从而能够设计开发出新的且更加有疗效的治疗药物。
[Abstract]:Cholesteryl Ester Transfer protein is a plasma glycoprotein. It mediates the transport of cholesterol ester Cholesteryl Esteryl (CEC) from high-density lipoprotein to low-density lipoprotein low-density lipoproteins (LDLs) and very low density lipoprotein very Low-density proteins (VLDLs). At the same time, the reverse transport of triglyceride triglyceride (TGs) reduces the transport of triglyceride. Blood concentration of anti-arteriosclerotic HDL, Therefore, inhibiting the transport process mediated by CETP would be a good method for the treatment of cardiovascular disease. The aim of the experiment was to study 41 CETP inhibitor molecules which had been reported to be highly active and representative. The Dock6.2 software was used. The molecular docking of the 41 compounds was carried out with 10 active sites around the proligand in the complex. According to the docking results, the bioactivity of the inhibitor itself was basically consistent with that of CETP docking. The potential binding sites for the interaction between inhibitors and receptors were preliminarily identified. Through the research of Dock docking, A class of N-N-disubstituted trifluoro-3-amino-2-propanol (CETP) inhibitor compounds with the best scoring and activity values were selected. In order to investigate the action sites and mechanism of these inhibitors during docking, In order to ensure the scientific and accuracy of docking results, we have successfully confirmed the effective active sites by using AutoDock software to complete more detailed molecular docking work. We have carried out a series of molecular dynamics simulations with the help of Amber software. The docking results showed that the active regions of inhibitor interacting with receptor CETP were mainly located in two hydrophobic regions, P _ 1 and P _ 2. These two active sites could effectively bind to the lipophilic side chains or groups of the compounds. The amino acid residues of Val421 and P2 play a key role in the formation of hydrophobic region. The amino acid residues Phe197 and Phe463 in P2 region have 蟺-蟺 double bond conjugation with ligand molecules. Other substituents such as hydrophobic substituents on the 1-3-phenoxy group also promote the inhibitory effect. The hydrophobicity of tetrafluoroethoxy phenyl at 3-position is better than that of a short substituent. The mechanism of small molecule action of receptor CETP and ligand inhibitor can successfully explain why different inhibitor structures have different inhibitory activities. We hope that these findings can provide some information for CETP related cardiovascular and cerebrovascular diseases. Useful information and guidance, It is possible to design and develop new and more effective therapeutic drugs.
【学位授予单位】：天津大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R341

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