一个组织型纤溶性溶解酶原激活剂(T-pa)非共价类抑制剂的药效模型

A Feature Based Pharmacophore for Tissue - type Plasminogen Activator non - covalent Inhibitor

为了研究组织型纤溶性溶解酶原激活剂(T-pa)的非共价类抑制剂的三维定量构效关系,本文采用分子模拟软件Catalyst 4.0(molecular simulation company)构建T-pa的非共价类抑制剂的三维药效模型。14个非共价类的抑制剂及其体外活性数据被用于构建此药效模型。此药效模型有3个疏水区特性,一个正离子化区特性和氢键供体区特性,且结构与活性相关系数为r=0.962。与T-pa的晶体结构比较,此药物模型在化学状态和疏水性上与其能很好的相匹配。且利用此模型查找到的抑制剂(bbzi14)的活性构象,与晶体结构中此抑制剂的结合构象基本一致。通过此药效集团模型反映的抑制剂与受体的相互作用模式,能为发现新型亲和配基和抑制剂提供有用的启示。

In order to explore the three-dimensional quantitative structure activity relationship (3D-qsar) of non-covalent inhibitors of tissue-type plasminogen activator (T-pa), a three-dimensional pharmacophore model has been built for T-panon-covalent inhibitors with the molecular simulation software CATALYST4.0 (Molecular Simulation Inc). The in Vitro T-pa inhibitory activity (Ki value) of 14 non-covalent inhibitors was used for pharmacophore generation. The best-found pharmacophore model involves three hydrophobic (Hp) features, one H-bond donor and one positive ionic feature. The model demonstrated a correlation of experiment and prediction Ki value of r = 0.96 . Conformations proposed for the ligand with the pharmacophore model is in good consistency with the one bound in crystal structure of the enzyme complex. The validation has also been tested in proposing the active conformation of a newly discovered inhibitor. The studying of interaction between the inhibitors and T-pa active site with the pharmacophore model could provide useful information for improving T-pa inhibitors or ligands.