Flexible ligand docking studies of matrix metalloproteinase inhibitors using Lamarckian genetic algorithm

ABSTRACT

As important therapeutic drug targets, matrix metalloproteinases [MMPs] have recently attracted great interest in the search for potent and selective inhibitors using computer-aided molecular modelling and docking techniques. Availability of more than 60 X-ray crystal structures or NMR solution structures related to MMPs in Protein Data Bank [PDB] of which more than half of them are in complex with various MMP inhibitors [MMPIs], provides a great opportunity for docking studies. In this study AutoDock 3.0.5 along with its LGA algorithm were used for automated flexible ligand docking of 32 MMPI-MMP complexes and docking accuracy and reliability of the estimated inhibition constants were evaluated. Twenty-six out of 32 docks had RMSD less than 3.0 A which is considered as well-docked, however, for the most of the cases [15 out of 27], predicted pKi values were considerably overestimated in comparison to experimental values. To improve pKi prediction regarding MMPI-MMP complexes, inclusion of at least one such a complex in calibration of empirical free energy function in the next release of AutoDock is highly recommended