A Predictive HQSAR Model for a Series of Tricycle Core Containing MMP-12 Inhibitors with Dibenzofuran Ring.

Jamal Shamsara,Ahmad Shahir-Sadr

doi:10.1155/2014/630807

Abstract

MMP-12 is a member of matrix metalloproteinases (MMPs) family involved in pathogenesis of some inflammatory based diseases. Design of selective matrix MMPs inhibitors is still challenging because of binding pocket similarities among MMPs family. We tried to generate a HQSAR (hologram quantitative structure activity relationship) model for a series of MMP-12 inhibitors. Compounds in the series of inhibitors with reported biological activity against MMP-12 were used to construct a predictive HQSAR model for their inhibitory activity against MMP-12. The HQSAR model had statistically excellent properties and possessed good predictive ability for test set compounds. The HQSAR model was obtained for the 26 training set compounds showing cross-validated q 2 value of 0.697 and conventional r 2 value of 0.986. The model was then externally validated using a test set of 9 compounds and the predicted values were in good agreement with the experimental results (r pred 2 = 0.8733). Then, the external validity of the model was confirmed by Golbraikh-Tropsha and r m 2 metrics. The color code analysis based on the obtained HQSAR model provided useful insights into the structural features of the training set for their bioactivity against MMP-12 and was useful for the design of some new not yet synthesized MMP-12 inhibitors.

Highlights

Matrix metalloproteinases (MMPs) family enzymes can degrade extracellular matrix components by their proteolytic activity which depends on catalytic zinc ion [1]
MMP-12 is an interesting therapeutic target overexpressed in inflammatory pathological conditions (such as respiratory system diseases including asthma and chronic obstructive pulmonary disorder (COPD)) [2]
The Y-randomization results indicated that the calculated q2 (−1.238, −0.303, −0.793, 0.081, and −0.146) and r2 (0.683, 0.088, 0.086, 0.241, and 0.126) for five random models are very low which confirm the internal validity of the generated HQSAR model

Summary

Introduction

Matrix metalloproteinases (MMPs) family enzymes can degrade extracellular matrix components by their proteolytic activity which depends on catalytic zinc ion [1]. The main role of macrophage metalloelastase (MMP-12) is degradation of elastin. Effectiveness of MMP-12 inhibitors in reducing inflammation in respiratory system has been shown [3, 4]. The active site is highly conserved among MMPs with the exception of a loop region called S1󸀠. S1󸀠 pocket in MMPs active sites varies slightly among MMPs in both sequence and structure [5]. Still the lack of selectivity remains as a main challenge for successfulness of MMPs inhibitors in clinical trials. In this study, a ligand based approach was used to modify the side chain in a series of MMP-12 inhibitors. A HQSAR study on a series of tricycle cores containing MMP-12 inhibitors was carried out

Methods

Results

Discussion

Conclusion