Molecular modeling of binding between amidinobenzisothiazoles, with antidegenerative activity on cartilage, and matrix metalloproteinase-3.
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 Zn(2+) 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.
Amadasi
Alessio
A
Dipartimento di Biochimica e Biologia Molecolare, Via G.P. Usberti 23/A, 43100 Parma, Italy.
Cozzini
Pietro
P
Incerti
Matteo
M
Duce
Elenia
E
Fisicaro
Emilia
E
Vicini
Paola
P
D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism; D002357:Cartilage Diseases / Q000188:drug therapy / Q000378:metabolism; D003198:Computer Simulation; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013844:Thiazoles; D019278:Matrix Metalloproteinase 3