Development of a receptor-based 3D-QSAR study for the analysis of MMP2, MMP3, and MMP9 inhibitors.
The ability of Gold software to predict the binding disposition of matrix metalloproteinase (MMP) inhibitors was evaluated using MMP3 and MMP8. The best procedure was subsequently employed to dock into MMP2, MMP3 and MMP9 nearly 70 compounds that were tested for their inhibitory activity against the three MMP subtypes. The best binding poses were used as an alignment tool for the development of 3D-QSAR studies. Evaluation of the three resulting 3D-QSAR models allowed us to indicate the ligand properties and residues important for activity and selectivity. MMP2 is an important anticancer drug target, while MMP3 and MMP9 are considered to be anti-targets for tumor pathologies. As such, our results could predict the binding affinities of new MMP2 inhibitors, providing additional information regarding the selectivity against MMP3 and MMP9. Furthermore, this strategy may be used also for the investigation of other MMPs.
Tuccinardi
Tiziano
T
Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.
Nuti
Elisa
E
Ortore
Gabriella
G
Rossello
Armando
A
Avramova
Stanislava I
SI
Martinelli
Adriano
A
D007527:Isoenzymes; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
D007527:Isoenzymes; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020782:Matrix Metalloproteinases