ABSTRACT
As part of a program aimed at the design and synthesis of constrained MMP inhibitors, a survey of the reported X-ray and NMR structures of MMP/inhibitor complexes was performed, revealing mutations of key amino acids at different subsites between MMPs. A comparative study of fully automated docking programs AutoDock and DOCK in closely approximating the X-ray crystal structures of ten selected MMP inhibitors was performed. AutoDock proved to be highly reliable, efficient and predictive for a set of inhibitors with less than six atom types.
Subject(s)
Drug Design , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Binding Sites/genetics , Computer Simulation , Crystallography, X-Ray , In Vitro Techniques , Macromolecular Substances , Magnetic Resonance Spectroscopy , Matrix Metalloproteinases/chemistry , Matrix Metalloproteinases/genetics , Matrix Metalloproteinases/metabolism , Models, Molecular , Mutagenesis, Site-Directed , Protease Inhibitors/metabolism , Software , ThermodynamicsABSTRACT
Saxitoxin at concentrations of 3 x 10(-8) to 3 x 10(-7) mole per liter blocks the conduction of lobster giant axon with no change in resting potential. Recovery of washed axons is faster in those that had been treated with saxitoxin than it is in those that were treated with tetrodotoxin. Peak transient increase in nerve membrane conductance is selectively blocked by saxitoxin with no change in late steady-state increase in conductance. The major mechanism of saxitoxin blockage is the same that of tetrodotoxin blockage.