MOLECULAR DOCKING AND 3D-QSAR ANALYSIS STUDIES OF MMP-12 INHIBITORS

摘要

Matrix metalloproteinase 12 (MMP-12) inhibitions is an important research topic because of its wide range of associated health implications. The interaction mode of a series of pyridinone compounds with MMP-12 has been studied using molecular docking and 3D-QSAR approaches. Flexible docking was used for the determination of active conformation and molecular alignment. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to develop 3D-QSAR models of 64 pyridinone-based compounds. The q2 values were 0.552and 0.542 for both CoMFA and CoMSIA models, respectively. The ability of these models was validated by 16 compounds of the test set. The resulting contour maps produced by the best CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series of compounds. FlexX were employed to dock the inhibitors into the active site of the MMP-12 and these docking studies revealed the vital interactions and binding conformation of the inhibitors. The results demonstrate that combination of ligand-based and receptor-based modeling is a powerful approach to build3D-QSAR models.