An integrated structure- and pharmacophore-based MMP-12 virtual screening.

MMP-12 belongs to a large family of proteases called matrix metalloproteinases (MMPs) that degrades elastin. The main pathologic role of MMP-12 overexpression was suggested to be associated with pathogenesis mechanism of inflammatory respiratory diseases and atherosclerosis. An integrated ligand- and structure-based virtual screening was employed in hope of finding inhibitors with new scaffolds and selectivity for MMP-12. Seven compounds among 18 experimentally tested compounds had a measurable effect on the inhibition of MMP-12 enzyme. Our results demonstrated the applicability of the developed pharmacophore model and selected crystal structure (PDB code: 3F17) to discover new MMP-12 inhibitors. The receptor structure was selected based on cross-docking results. Here, we report the discovery of new class of MMP-12 inhibitors that could be used for lead optimization. For the inhibition of MMP-12, the significance of its interactions with the catalytic residues Glu219 and Ala182 was emphasized through the inspection of the docking poses.