Identification and Biological Validation of MMP-12 Inhibitors Guided by Pharmacophore-Based Virtual Screening and Docking Studies.

Matrix metalloproteinase-12 (MMP-12) is a zinc-dependent enzyme involved in extracellular matrix remodeling and inflammatory processes. In this study, a ligand-and structure-based design approaches including pharmacophore modeling and molecular docking were employed to identify potent MMP-12 inhibitors. Indole-3-acetic acid derivatives were prioritized based on their fit to a pharmacophore model and strong predicted interactions within the MMP-12 catalytic site. Selected compounds were synthesized and evaluated using a colorimetric enzyme inhibition assay. Docking studies revealed favorable binding energies and key interactions with active-site residues such as HIS-218, PHE-237, GLU-219, and LEU-181. Enzyme inhibition assays validated the activity of the indole-3-acetic acid scaffold, with four leading candidates (C23-C26) demonstrating over 94% inhibition of MMP-12. The integration of in silico predictions with experimental testing guided the identification of indole-3-acetic acid as a promising scaffold, underscoring the utility of this design approach for scaffold prioritization. These findings establish indole-3-acetic acid as a promising scaffold for further development of MMP-12 inhibitors and provide a foundation for future biological evaluation.