Identification of Broad-Spectrum MMP Inhibitors by Virtual Screening.

Gerard Pujadas,Miquel Mulero,María José Ojeda-Montes,Santiago Garcia-Vallvé,Doretta Cuffaro,Elisa Nuti,Aleix Gimeno,Armando Rossello,Raúl Beltrán-Debón

doi:10.3390/molecules26154553

Abstract

Matrix metalloproteinases (MMPs) are the family of proteases that are mainly responsible for degrading extracellular matrix (ECM) components. In the skin, the overexpression of MMPs as a result of ultraviolet radiation triggers an imbalance in the ECM turnover in a process called photoaging, which ultimately results in skin wrinkling and premature skin ageing. Therefore, the inhibition of different enzymes of the MMP family at a topical level could have positive implications for photoaging. Considering that the MMP catalytic region is mostly conserved across different enzymes of the MMP family, in this study we aimed to design a virtual screening (VS) workflow to identify broad-spectrum MMP inhibitors that can be used to delay the development of photoaging. Our in silico approach was validated in vitro with 20 VS hits from the Specs library that were not only structurally different from one another but also from known MMP inhibitors. In this bioactivity assay, 18 of the 20 compounds inhibit at least one of the assayed MMPs at 100 μM (with 5 of them showing around 50% inhibition in all the tested MMPs at this concentration). Finally, this VS was used to identify natural products that have the potential to act as broad-spectrum MMP inhibitors and be used as a treatment for photoaging.

Highlights

The extracellular matrix (ECM) consists of a network of macromolecules which provide physical support to the cell, and transmit mechanical and molecular signals to communicate with the surrounding cells [1]
The approach described was applied to different compound libraries to: (a) validate the approach in silico; (b) validate the approach in vitro and (c) use the approach to identify natural products that may be broad-spectrum Matrix metalloproteinases (MMPs) inhibitors
After validating the performance of this virtual screening (VS) workflow in vitro with some selected VS hits obtained from the Specs library, we applied it to a subset of the Reaxys containing natural products with a molecular weight between 300 and 600 Da

Summary

Introduction

The extracellular matrix (ECM) consists of a network of macromolecules which provide physical support to the cell, and transmit mechanical and molecular signals to communicate with the surrounding cells [1]. The three major components of the ECM are: (a) glycosaminoglycans, usually covalently linked to protein in the form of proteoglycans, large and highly charged polysaccharides that form a highly hydrated gel-like substance, which resists compressive forces and allows nutrients, metabolites and hormones to diffuse; (b) fibrous proteins (primarily members of the collagen family), which give the ECM both structure and elasticity; and (c) a large and varied assortment of glycoproteins, which help cells migrate, settle and differentiate in the appropriate locations. As important as the ability of cells to build and bind to the ECM is their ability to degrade it. Matrix metalloproteinases (MMPs) are the family of proteases that are mainly responsible for degrading ECM components. These enzymes are dependent on Ca2+ or Zn2+ and degrade different components of the ECM with different specificity [1]. MMP inhibition has been suggested as an important therapeutic tool to fight these diseases [10,11,12]

Objectives

Methods

Results

Conclusion