CADD法在降血脂药物研究中的应用

目的：利用计算机辅助新药设计(Computer Aided Drug Design，CADD)技术中的受体图像法，对不同类型降血脂药物的化学结构及甘草次酸类的降血脂药效结构进行模型化研究，并初步探讨甘草次酸类的降血脂药理作用机制。方法：利用计算机程序EMO(分子力学程序)和GEOMOS(量子力学)以及Semi-empirical PM3方法，对4种不同类型的32个具有降血脂活性的分子进行分析。通过分子能量的降低和空间结构的优化处理，测定和计算这些分子的有关几何性、电性和能量参数。然后对优化后分子进行类型内重叠和有关参数的类型间对比观察，预测各类分子的共同药效结构和功能基团。分子重叠的可行性用参数RMS(Root Meam Square)进行判断。结果：分别获得32个降血脂活性分子的4种不同特征的药效基本结构图像，并发现甘草酸类(如18β-甘草次酸)与苯氧乙酸类(fibrates)分子的优化空间构型中，存在类似的特定结构片段，相应原子和原子团的电荷密度分布(net charges)、3个电荷中心分布及其相间距离具有可观的相似性。说明在甘草酸类的优化空间结构上可能具有与苯氧乙酸类药物类似的药效结构片段存在，甘草次酸及18-脱氢甘草次酸的铵盐降低71％的甘油三酯和51％胆固醇浓度。结论：甘草次酸类可能具有与苯氧乙酸类类似的降血脂作用机理，同时与苯氧乙酸类的作用特点类似。

CADD techniques in Hypolipidemic drug research

Objective: To identify the pharmacophore moieties of hypolipidemic drugs, we developed the receptor mapping method in CADD (Computer Aided Drug Design) techniques. Methods: Using molecular modelling program EMO and semi-empirical PM3 method (Geomos software), to study 4 hypolipidemic series. After global energy minimization of 32 compounds and superposition of their optimized geometry within each chemical class, we have identified common molecular characteristics as geometrical, electronic and energetic parameters. A superposition was achieved for the optimized geometry of each hypolipidemic drugs series and a comparison proceed also between the related parameters of each family. The quality of superposition was validated by their Root Mean Square (RMS) data, then their pharmacophoric characteristics were identified. Results: We obtained 4 kinds of pharmacophoric structure for 32 hypolipidemic compounds, and observed, on the geometrical structures of GA derivatives, a structural domain corresponding to the pharmacophore of fibrates, with considerable electronic and geometric-similarity. Our results suggest that, the hypolipidemic principle of GA derivatives could proceed mainly from a mechanism similar to fibrates. Cholesterol and Inglycerides decrease by respectively 51 % and 71 %. Conclusion: It could be related to the pharmacological activity of GA derivatives in atherosclerotic rabbits. This is similar to fibrates.