An overview of matrix metalloproteinase-12 in multiple disease conditions, potential selective inhibitors, and drug designing strategies.

Matrix metalloproteases (MMPs) are the proteolytic enzymes accountable for extracellular matrix (ECM) modification through their Zn-dependent catalytic activity. Among these, MMP-12 is one of the crucial MMPs that contributes to various disease states including different types of cancers and other major pathophysiological conditions including COPD, asthma, emphysema, skin diseases, arthritis, vascular diseases, and neurological disorders. The majority of the MMP-12 inhibitors should have three constitutional pharmacophoric features (i.e., a hydrophobic group to occupy the S1' pocket, a zinc-binding motif for chelating to the catalytic Zn ion present at the catalytic site, and a flexible and hydrogen bond forming linker region between the S1' pocket substituent and the zinc chelating group for interacting with the catalytic and Ω-loop amino acid residues). This review mainly focuses on the various roles of MMP-12 in different diseases along with the structural comparison with other MMPs as well as promising and MMP-12-selective inhibitors and molecular modeling studies performed on MMP-12 inhibitors. Therefore, this review will provide comprehensive information to the researchers for designing effective and MMP-12-selective inhibitors for therapeutic advancement in the future.