A Feature Based Pharmacophore for Tissue - type Plasminogen Activator non - covalent Inhibitor
Yang Sheng-li · Jisuanji yu yingyong huaxue · 2002
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.