Modified AutoDock for accurate docking of protein kinase inhibitors.
Protein kinases are an important class of enzymes controlling virtually all cellular signaling pathways. Consequently, selective inhibitors of protein kinases have attracted significant interest as potential new drugs for many diseases. Computational methods, including molecular docking, have increasingly been used in the inhibitor design process [1]. We have considered several docking packages in order to strengthen our kinase inhibitor work with computational capabilities. In our experience, AutoDock offered a reasonable combination of accuracy and speed, as opposed to methods that specialize either in fast database searches or detailed and computationally intensive calculations. However, AutoDock did not perform well in cases where extensive hydrophobic contacts were involved, such as docking of SB203580 to its target protein kinase p38. Another shortcoming was a hydrogen bonding energy function, which underestimated the attraction component and, thus, did not allow for sufficiently accurate modeling of the key hydrogen bonds in the kinase-inhibitor complexes. We have modified the parameter set used to model hydrogen bonds, which increased the accuracy of AutoDock and appeared to be generally applicable to many kinase-inhibitor pairs without customization. Binding to largely hydrophobic sites, such as the active site of p38, was significantly improved by introducing a correction factor selectively affecting only carbon and hydrogen energy grids, thus, providing an effective, although approximate, treatment of solvation.
Buzko
Oleksandr V
OV
Department of Cellular and Molecular Pharmacology, University of California, San Francisco 94143-0450, USA. buzko@cmp.ucsf.edu
Bishop
Anthony C
AC
Shokat
Kevan M
KM
D000244:Adenosine Diphosphate / Q000737:chemistry / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D020134:Catalytic Domain; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D009154:Mutation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D012984:Software; D013816:Thermodynamics; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases
D004791:Enzyme Inhibitors; D008024:Ligands; D047428:Protein Kinase Inhibitors; D000244:Adenosine Diphosphate; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases