Abstract
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.
Highlights
Matrix metalloproteinases are zinc-containing enzymes capable of degrading all components of the extracellular matrix
To extend the bioinorganic approach in a way that properly accounts for Matrix metalloproteinases (MMPs)-2 and MMP-3 dynamics, we here investigate the predicted binding modes and affinities of the zinc-binding group (ZBG)-AM2, ZBG-AM-5, and ZBG-AM-6 compounds docked into multiple structures extracted from MMP-2 and MMP-3 molecular dynamics (MD) simulations
The purpose of this study is to extend the bioinorganic approach originally pioneered by Puerta et al [29] in a way that properly accounts for MMP-2 and MMP-3 dynamics
Summary
Matrix metalloproteinases are zinc-containing enzymes capable of degrading all components of the extracellular matrix. 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. A number of studies have suggested that the MMP active site is highly flexible, leading some to speculate that differences in activesite flexibility among the different MMPs could explain specificity In their previous work, Yuan et al [31] studied the backbone amide dynamics of the MMP-3 catalytic domain using 15N NMR relaxation measurements. By directly measuring the S1¢ pocket volumes of MMP structures extracted from MD simulations, Durrant et al [32] further confirmed that MMP-3 tends to be either fully open or closed, while MMP-2 is more apt to adopt intermediate states
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