title: SDOCKER: a method utilizing existing X-ray structures to improve docking accuracy.
abstract: This paper introduces a new strategy for structure-based drug design that combines high-quality docking with data from existing ligand-protein cocrystal X-ray structures. The main goal of SDOCKER, a new algorithm that implements this strategy, is docking accuracy improvement. In this new paradigm, simulated annealing molecular dynamics is used for conformational sampling and optimization and an additional similarity force is applied on the basis of the positions of ligands from X-ray data that focus the sampling on relevant regions of the active site. Because the structural information from both the ligand and protein active site is included, this approach is more effective in finding the optimal conformation for a ligand-protein complex than the classical docking or similarity overlays. Interestingly, it was found that a 3D similarity-only approach gives comparable docking accuracy to the regular force field approach used in classical docking, given the final structures are minimized in the presence of the protein. The combination of both, as implemented in SDOCKER, is shown here to be more accurate. A significant improvement in docking accuracy has been observed for three different test systems. Specifically an improvement of 10%, 17.5%, and 10% is seen for 37 HIV-1 protease, 32 thrombin, and 23 CDK2 ligands, respectively, compared to docking using the force field alone. In addition, SDOCKER's accuracy performance dependence on the similarity template is discussed. The strategy of utilizing existing ligand X-ray information should prove effective in light of the multitude of structures available from structural genomics approaches.
authors.affiliation: Lilly Research Labs, Lilly Corporate Center, DC 1513, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Wu
authors.forename: Michal
authors.initials: M
authors.lastname: Vieth
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D004791:Enzyme Inhibitors / Q000737:chemistry; D016333:HIV Protease / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011506:Proteins / Q000737:chemistry*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D011506:Proteins; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D013917:Thrombin; D016333:HIV Protease