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 him(] 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 oil the set of 37 protein-ligand complexes has shown file 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. oil the same set of complexes. (C) 2009 Wiley periodicals, Inc. J Comput Chem 31: 1080-1092. 2010