Using the Semiempirical Quantum Mechanics in Improving the Molecular Docking: A Case Study with CDK2.

In this study, we use some modified semiempirical quantum mechanics (SQM) methods for improving the molecular docking process. To this end, the three popular SQM Hamiltonians, PM6, PM6-D3H4X, and PM7 are employed for geometry optimization of some binding modes of ligands docked into the human cyclin-dependent kinase 2 (CDK2) by two widely used docking tools, AutoDock and AutoDock Vina. The results were analyzed with two different evaluation metrics: the symmetry-corrected heavy-atom RMSD and the fraction of recovered ligand-protein contacts. It is shown that the evaluation of the fraction of recovered contacts is more useful to measure the similarity between two structures when interacting with a protein. It was also found that AutoDock is more successful than AutoDock Vina in producing the correct ligand poses (RMSD≤2.0 Å) and ranking of the poses. It is also demonstrated that the ligand optimization at the SQM level improves the docking results and the SQM structures have a significantly better fit to the observed crystal structures. Finally, the SQM optimizations reduce the number of close contacts in the docking poses and successfully remove most of the clash or bad contacts between ligand and protein.