Pyrone-Based Inhibitors of Metalloproteinase Types 2 and 3 May Work as Conformation- Selective Inhibitors

These authors contributed equally. 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 bioinor-ganic 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 inhibi-tors, AM-6, had approximately 2500-fold selectiv-ity 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 flexibil-ity may explain inhibitor selectivity. To extend the bioinorganic approach in a way that accounts for MMP-2 and MMP-3 dynamics, we here inves-tigate the predicted binding modes and ener-gies of AM-6 docked into multiple structures extracted from matrix-metalloproteinase molecu-lar 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 sim-ilar inhibitors likely select for and stabilize only a subpopulation of all matrix-metalloproteinase conformations sampled by the apo protein. Con-sequently, 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. Key words: computer-aided drug design, docking, inhibitors, matrix metalloproteinases, protein flexibilit