Modeling and docking studies of matrix metalloproteinases

Modeling and docking studies were undertaken to investigate and understand the interactions of zinc-dependent matrix metalloproteinases (MMPs) with small molecular inhibitors that are potential drug candidates for a wide range of diseases such as cancer, arthritis, and multiple sclerosis. A particular emphasis was given on the zinc ion in the active site of MMP.; These studies indicated that modeling and docking of zinc metalloproteinases remains a challenge due to the various polyhedral coordination geometries assumed by zinc and the lack of an appropriate force field capable of correctly predicting the behavior of ligands for these enzymes. Comparative modeling studies of the zinc binding site of MMP showed that quantum calculation with the B3LYP/6-31G* method is an effective and reliable strategy to probe the interactions between zinc and exogenous ligands. Optimization of the zinc parameters for AutoDock greatly improved the docking accuracy at the zinc binding site as well as the prediction of binding free energy. The optimized zinc charge was close to the charge predicted by ab initio quantum calculation indicating that a more realistic zinc charges may be used in docking instead of assigning full formal charges.; In addition, comparative docking studies of five widely used docking approaches including AutoDock, DOCK, GOLD, FlexX, and DrugScore showed that proper zinc coordination geometry is a prerequisite for the success of docking the ligands to zinc metalloproteinases. More than 75% of docked poses with RMSD less than 2 A were found to have appropriate ZBG binding, but if the ZBG binding was poor, about 95% of poses failed to dock correctly. Subdividing the ligands into groups based on ZBG showed significant improvement to the scoring reliability and, while combined with consensus scoring, was particularly effective to the docking performance.; Virtual screening (VS) of NCI and Maybridge databases has been carried out for the discovery of novel leads of gelatinase. Using a hierarchical screening strategy combining the ZBG filtering and subset-based X-CSOCRE scoring, several potential MMP inhibitors have been validated. Moreover, a urea-like group was identified to bind to zinc with bidentate mode, providing a novel ZBG for MMP inhibitor design.