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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 study the three-dimensional quantitative structure-activity relationship of non-covalent inhibitors of tissue-type plasminogen activator (T-pa), a molecular simulation software, Catalyst 4.0 (molecular simulation company) Three-dimensional pharmacodynamic model of inhibitors. Fourteen non-covalent inhibitors and their in vitro activity data were used to construct this efficacy model. The pharmacodynamic model has three hydrophobic regions, one cationization region and hydrogen bond donor region. The correlation coefficient between structure and activity is r = 0.962. Compared with the crystal structure of T-pa, this drug model is well matched in its chemical state and hydrophobicity. The active conformation of the inhibitor (bbzi14) found by this model is basically the same as the binding conformation of this inhibitor in the crystal structure. The mode of interaction between the inhibitor and the receptor reflected by this pharmacophore model can provide useful enlightenment for discovering novel affinity ligands and inhibitors.