基于结构的组合库设计在AⅡ受体拮抗剂中的应用

Application of structure-based combinatorial library design in AII receptor antagonist

目的:研究基于结构的组合库设计及筛选方法在血管紧张素Ⅱ受体拮抗剂中的应用。方法:根据受体结合理论,应用基于结构设计的方法建立了非肽类血管紧张素Ⅱ受体拮抗剂的虚拟组合化学库,用 Lipinski 规则和 QSAR 模型对库成员进行筛选。结果:计算库成员中72个新的咪唑类化合物的结构参数,基于结构参数,用 Lipinski 规则进行药动性质筛选,用 QSAR模型进行药效活性筛选,得到6个药动和药效性质都较好的化合物。结论:基于结构设计的虚拟组合化学库设计及筛选方法是从受体作用机理出发提取组合库的构建单元,因此在保证库成员分子多样性的条件下同时确保了库成员分子药理结构的合理性,以及库成员分子结构的类药性。

Objective：Design and screening of virtual combinatorial chemical library for angiotensin Ⅱ receptor antagonists was discussed. Methods： Based on the receptor binding theory, and structural design approach was employed to build the virtual combinatorial chemical library of angiotensin Ⅱ receptor antagonists. The Lipinski ruler together with the QSAR model was used to screening the molecule in library. Results：Calculated the structural parameters of each molecule in library, according to the structural parameters, pharmacokinetic properties of molecules were screened by Lipinski ruler,the biological activity of molecules were screened by established QSAR model. Six molecules with potent higher pharmacokinetic property and better biological activity were obtained. Conclusion：The structural design approach of virtual combinatorial chemical library derived from the receptor binding theory, which ensured the molecules in library with diversity,like - drug property and the reasonable structure.