A Ligand‐Based Molecular Modeling Study on Some Matrix Metalloproteinase‐1 Inhibitors Using Several 3D QSAR Techniques.

Abstract

Some three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been constructed using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) for a series of 84 proline-based plus 12 structurally more diversified nonproline matrix metalloproteinase inhibitors. The structures of these inhibitors were built from a structure template extracted from the crystal structure of stromelysin. The structures built were divided into the training and test sets for both the CoMFA and CoMSIA analyses for each being composed of 60 and 24 inhibitors, respectively. The structures in the training set were aligned using some alignment rules derived from the analysis of the Ligplot program on a recent crystal structure of ligand-collagenase-1 complex. Some stepwise CoMSIA's were performed on the aligned training set on which the best CoMFA result was obtained. The best CoMSIA model was identified from the stepwise results, and the corresponding pharmacophore features were used for the construction of a pharmacophore hypothesis by the Catalyst 4.9 program. The training set was extended to include 11 structurally more diversified and nonproline inhibitors. To construct a pharmacophore hypothesis, the conformation of 60 structurally aligned proline-based inhibitors was fixed, while that of the 11 structurally more diversified nonproline inhibitors was allowed to vary during the hypothesis construction process. It was found that the predicted activities by the top hypothesis constructed for both the training and test sets were as good in statistics as those predicted by the best CoMSIA model from which the hypothesis was derived. The top hypothesis was mapped onto the structures of several highly active inhibitors selected from both the training and test sets. The goodness of mapping on each inhibitor was found to be correlated well with the activity of each inhibitor.

QSAR Studies on Hydroxamic Acids: A Fascinating Family of Chemicals with a Wide Spectrum of Activities

“…Tsai and Linn made a CoMFA and CoMSIA study on a series of 84 proline-based compounds with general structure as 28 plus some structurally diversified nonproline compounds acting as MMP-1 inhibitors. Their CoMFA study prominently described the favorable steric (S) and electrostatic (E) regions, while CoMSIA described favorable hydrophobic (H), steric (S), and H-bond acceptor (A) regions.…”

“…Magenta contours represent favor, while red contours represent disfavor regions for H-bond acceptor. Reprinted with permission from ref . Copyright 2004 American Chemical Society.…”

“…215 That the hydrophobic, electrostatic, and steric interactions play important roles in MMP inhibition have been visualized by some molecular modeling studies. 200,202,216 Verma and Hanch 172 also reported 2D QSAR studies on several series of hydroxamates acting as MMP inhibitors just to conclude that hydrophobicity and molar refractivity of compounds play an important role in MMP inhibition. In his recent communication, Verma 177 beautifully summarized all 2D QSARs (Table 8) on different categories of hydroxamates (Figure 41) to have a comparative view of drug−receptor interactions of all hydroxamates and to conclude that among physicochemical properties, the greatest contribution in MMP inhibition is of hydrophobicity followed by the electronic properties of substituents.…”