Evaluation of the Inhibitory Potential of Matrix Metalloproteinase Inhibitors against the Catalytic Site of MMP Isoforms- An in silico Study

Matrix metalloproteinases (MMP) has long since known to be a promising drug targets particularly in the context of cancer. They play crucial role in several cellular functions like cell proliferation, adhesion, differentiation, apoptosis etc making them valuable tool in cancer prognosis. However the various isoforms of MMPs makes it challenging to obtain a selective inhibition of MMPs. These functions of MMPs are largely dependent on Zn as a cofactor and therefore the search for high-affinity zinc binding groups that effectively inhibit the catalytic site is believed to serve as a template in designing effective inhibitors. In the current study we have computationally evaluated the selectivity and binding potential of 16 MMP inhibitors by docking the drugs towards the zinc binding groove of 11 matrix metalloproteinases. The docking results were evaluated based on selectivity, hydrogen bond interactions with the catalytic site residue, and zinc chelation ability of the drugs. Our results revealed fludrocortisone acetate, hydrocortisone and marimastat exhibited comparatively better in selectivity, affinity towards catalytic site and zinc ion coordination respectively. The combined features of the drugs indicated the presence of hydroxyl and amino groups that favored hydrogen bonds and monodentate coordination of zinc; the presence of fluorine atom to contribute to the selectivity of the drugs. Further validation of these drugs through simulation and in vitro studies could offer valuable findings that contribute to selective inhibition of matrix metalloproteinases.