Molecular modeling of binding between amidinobenzisothiazoles, with antidegenerative activity on cartilage, and matrix metalloproteinase-3 Original Research Article

The aim of the work was to investigate the mechanism of binding between human metalloproteinase-3 (MMP-3) and new compounds belonging to the benzisothiazolylamidines class. In vitro tests suggest that these molecules, endowed with antinflammatory and cartilage antidegenerative activity, could act as ligands toward MMP-3. In lack of experimental structural informations, we performed molecular docking simulations to probe the interactions of benzisothiazolylamidines with matrix metalloproteinase-3, using the docking package GOLD and the software HINT as a post-process scoring function. Both GOLD and HINT predicted a binding mode for the compounds under analysis within the hydrophobic S1′ pocket of MMP-3, without interaction with the catalytic Zn2+ ion. The scores assigned by the programs to the interaction between the tested benzisothiazolylamidines and human MMP-3 were consistent with a potential direct enzyme inhibitory activity. The highest affinity was predicted for the N–(benzo[d]isothiazol-3-yl)-4-chlorobenzamidine (2), emerged as the most active derivative also in the in vitro tests.