3D-QSAR studies on a diverse set of heterocyclic MMP inhibitors

Abstract

We have performed three dimensional quantitative structure activity relationship (3D-QSAR) studies on a set of pyridinone derivatives acting as MMP inhibitors. We have carried out the Study using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) approaches. Ligand molecular superimposition on the template structure was performed by the database alignment method. We have validated the training set of 47 molecules with a test set of 14 molecules for the improved predictivity of the model. CoMFA model yielded the best predictive values q²_cv, 0.876; r² (non-cross-validated square of correlation coefficient), 0.968; F value, 244.63; r²_bs, 0.977 with five components, and standard error of estimate (SEE), 0.055. The CoMSIA model yielded q²_cv, 0.829; r², 0.983; F value, 383.035; r²_bs, 0.986  with six components and SEE of 0.0041. We have analyzed the contour maps obtained from the study to reveal several key features responsible for the activity trends of inhibitors. The present study will further guide the design of novel, potent and selective MMP inhibitors.