These authors contributed equally.
Pyrone-Based Inhibitors of Metalloproteinase Types 2 and 3 May Work as Conformation-Selective Inhibitors
Article first published online: 20 JUN 2011
© 2011 John Wiley & Sons A/S
Chemical Biology & Drug Design
Volume 78, Issue 2, pages 191–198, August 2011
How to Cite
Durrant, J. D., de Oliveira, C. A. F. and McCammon, J. A. (2011), Pyrone-Based Inhibitors of Metalloproteinase Types 2 and 3 May Work as Conformation-Selective Inhibitors. Chemical Biology & Drug Design, 78: 191–198. doi: 10.1111/j.1747-0285.2011.01148.x
- Issue published online: 13 JUL 2011
- Article first published online: 20 JUN 2011
- Accepted manuscript online: 24 MAY 2011 07:19PM EST
- Received 5 April 2011, revised 7 May 2011 and accepted for publication 11 May 2011
- computer-aided drug design;
- matrix metalloproteinases;
- protein flexibility
Matrix metalloproteinases are zinc-containing enzymes capable of degrading all components of the extracellular matrix. Owing to their role in human disease, matrix metalloproteinase have been the subject of extensive study. A bioinorganic approach was recently used to identify novel inhibitors based on a maltol zinc-binding group, but accompanying molecular-docking studies failed to explain why one of these inhibitors, AM-6, had approximately 2500-fold selectivity for MMP-3 over MMP-2. A number of studies have suggested that the matrix-metalloproteinase active site is highly flexible, leading some to speculate that differences in active-site flexibility may explain inhibitor selectivity. To extend the bioinorganic approach in a way that accounts for MMP-2 and MMP-3 dynamics, we here investigate the predicted binding modes and energies of AM-6 docked into multiple structures extracted from matrix-metalloproteinase molecular dynamics simulations. Our findings suggest that accounting for protein dynamics is essential for the accurate prediction of binding affinity and selectivity. Additionally, AM-6 and other similar inhibitors likely select for and stabilize only a subpopulation of all matrix-metalloproteinase conformations sampled by the apo protein. Consequently, when attempting to predict ligand affinity and selectivity using an ensemble of protein structures, it may be wise to disregard protein conformations that cannot accommodate the ligand.