Effective handling of induced-fit motion in flexible docking

For structure-based drug design, where various ligand structures need to be docked to a target protein structure, a docking method that can handle conformational. flexibility of not only the ligand, but also the protein, is indispensable. We have developed a simple and effective approach for dealing with the local induced-fit motion of the target protein, and implemented it in our docking tool, ADAM. Our approach efficiently combines the following two strategies: a vdW-offset grid in which the protein cavity is enlarged uniformly, and structure optimization allowing the motion of ligand and protein atoms. To examine the effectiveness of our approach, we performed docking validation studies, including redocking in 18 test cases and foreign-docking, in which various ligands from foreign crystal structures of complexes are docked into a target protein structure, in 22 cases (on five target proteins). With the original ADAM, the correct docking modes (RMSD < 2.0 angstrom) were not present among the top 20 models in one case of redocking and four cases of foreign-docking. When the handling of induced-fit motion was implemented, the correct solutions were acquired in all 40 test cases. In foreign-docking on thymidine kinase, the correct docking modes were obtained as the top-ranked solutions for all 10 test ligands by our combinatorial approach, and this appears to be the best result ever reported with any docking tool. The results of docking validation have thus confirmed the effectiveness of our approach, which can provide reliable docking models even in the case of foreign-docking, where conformational. change of the target protein cannot be ignored. We expect that this approach will contribute substantially to actual drug design, including virtual screening.