SCIGRESS - Case Studies - Calculation of Binding Affinities for Stromelysin-1 (MMP-3) Inhibitors Using a Linear Scaling Semi-empirical Quantum Chemistry Method
Johnson & Johnson
Calculations done using CAChe
Stromelysin-1 is a matrix metalloproteinase (MMP-3). MMPs are zinc containing proteins associated with a variety of inflammatory, malignant and degenerative diseases and are thus attractive targets for drug development. Modeling of interactions between potential inhibitors of MMP-3 is hindered, however, by the fact that a proton shift and charge transfer occurs within the active site of the protein, ultimately resulting in a covalent Meta-Ligand (M-L) bond. Standard docking simulations model this binding interaction poorly.
Researchers at Johnson & Johnson utilized Scigress Explorer (BioMedCAChe) to model the binding affinity of potential MMP-3 inhibitors using MOZYME, the proprietary linear scaling MO procedure, and COSMO solvation energies. They were able to model directly the metal center in the active site and the covalent M-L bond and thus account for the charge transfer and proton transfer which occurs during binding. In addition, the technique was found be useful for modeling the interactions of diverse ligands within the MMP-3 active site. This technique holds promise for dealing with binding interactions across a variety of classes of organometallic enzymes.
To find more information please refer to mozyme_binding_energies.zip.
Calculation of the Binding Affinities for Stromelysin-1 (MMP-3) Inhibitors Using a Linear Scaling Semi-Empirical Quantum Chemistry Method, Jian Li & Charles H. Reynolds, Gordon Conference on Computer-aided Drug Design, July 2003, Tilton, NH