Docking studies of matrix metalloproteinase inhibitors: zinc parameter optimization to improve the binding free energy prediction.

Docking of metalloproteinase inhibitors remains a challenge due to the zinc multiple coordination geometries and the lack of appropriate force field parameters to model the metal/ligand interactions. In this study, we explore the docking accuracy and scoring reliability for the docking of matrix metalloproteinase (MMP) inhibitors using AutoDock 3.0. Potential problems associated with zinc ion were investigated by docking 16 matrix metalloproteinase ligands to their crystal structures. A good coordination between the zinc binding group (ZBG) and the zinc was shown to be a prerequisite for the ligand to fit the binding site. A simplex optimization of zinc parameters, including zinc radius, well depth, and zinc charges, was performed utilizing the 14 MMP complexes with good docking. The use of optimized zinc parameters (zinc radius: 0.87 A; well depth: 0.35 kcal/mol; and zinc charges: +0.95 e) shows improvement in both docking accuracy at the zinc binding site and the prediction of binding free energies. Although further improvement in the docking procedure, particularly the scoring function is needed, optimization of zinc parameters provides an efficient way to improve the performance of AutoDock as a drug discovery tool.