Flexible ligand docking: A multistep strategy approach

A flexible ligand docking protocol based on a divide-and-conquer strategy i s investigated. This approach first separates total search space into confo rmation and orientation space. It uses a grid-based method to sample the co nformation of an unbound ligand and to select the low-energy conformers. Ri gid docking is then carried out to locate the low-energy binding orientatio ns for these conformers. These docking structures are subsequently subjecte d to structure refinement including molecular mechanics minimization, confo rmational scanning at the binding site and a short period of molecular dyna mics-based simulated annealing. This approach has been applied to twelve li gand-protein complexes with three to sixteen rotatable bonds. The docked lo west-energy structures have root mean square deviations ranging from 0.64 A ngstrom to 2.01 Angstrom with respect to the corresponding crystal structur es. The effect of atomic charges and van der Waals parameters on the dockin g results, and the role of the dielectric constant in the conformation samp ling are discussed in detail. A fragment-based docking approach that takes advantages of the divide-and-conquer strategy has also been explored and th e results are compared with those produced by a whole molecule-based approa ch. Proteins 1999;36:1-19. (C) 1999 Wiley-Liss, Inc.