Blind docking method combining search of low-resolution binding sites with ligand pose refinement by molecular dynamics-based global optimization

This study describes the development of a new blind hierarchical docking method, bhDock, its implementation, and accuracy assessment. The bhDock method uses two-step algorithm. First, a comprehensive set of low-resolution binding sites is determined by analyzing entire protein surface and ranked by a simple score function. Second, ligand position is determined via a molecular dynamics-based method of global optimization starting from a small set of high ranked low-resolution binding sites. The refinement of the ligand binding pose starts from uniformly distributed multiple initial ligand orientations and uses simulated annealing molecular dynamics coupled with guided force-field deformation of protein-ligand interactions to find the global minimum. Assessment of the bhDock method on the set of 37 protein-ligand complexes has shown the success rate of predictions of 78%, which is better than the rate reported for the most cited docking methods, such as AutoDock, DOCK, GOLD, and FlexX, on the same set of complexes.