title: Toward the virtual screening of Cdc25A phosphatase inhibitors with the homology modeled protein structure.
abstract: Cdc25 phosphatases have been considered as attractive drug targets for anticancer therapy due to the correlation of their overexpression with a wide variety of cancers. As a method for the discovery of novel inhibitors of Cdc25 phosphatases, we have evaluated the computer-aided drug design protocol involving the homology modeling of Cdc25A and virtual screening with the two docking tools: FlexX and the modified AutoDock program implementing the effects of ligand solvation in the scoring function. The homology modeling with the X-ray crystal structure of Cdc25B as a template provides a high-quality structure of Cdc25A that enables the structure-based inhibitor design. Of the two docking programs under consideration, AutoDock is found to be more accurate than FlexX in terms of scoring putative ligands. A detailed binding mode analysis of the known inhibitors shows that they can be stabilized in the active site of Cdc25A through the simultaneous establishment of the multiple hydrogen bonds and the hydrophobic interactions. The present study demonstrates the usefulness of the modified AutoDock program as a docking tool for virtual screening of new Cdc25 phosphatase inhibitors as well as for binding mode analysis to elucidate the activities of known inhibitors.
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-Dong, Kwangjin-Ku, Seoul 143-747, Korea. hspark@sejong.ac.kr
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Jeon
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D012984:Software; D040681:Structural Homology, Protein; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D011506:Proteins; D020687:cdc25 Phosphatases