title: Receptor-based virtual ligand screening for the identification of novel CDC25 phosphatase inhibitors.
abstract: CDC25 phosphatases play critical roles in cell cycle regulation and are attractive targets for anticancer therapies. Several small non-peptide molecules are known to inhibit CDC25, but many of them appear to form a covalent bond with the enzyme or act through oxidation of the thiolate group of the catalytic cysteine. Structure-based virtual ligand screening computations were performed with FRED, Surflex, and LigandFit, a compound collection of over 310,000 druglike molecules and the crystal structure of CDC25B in order to identify novel classes of ligands. In vitro experiments carried out on a selected list of 1500 molecules led to the discovery of 99 compounds able to inhibit CDC25B activity at 100 microM. Further docking computations were applied, allowing us to propose a binding mode for the most potent molecule (IC50 = 13 microM). Our best compounds represent promising new classes of CDC25 inhibitors that also exhibit antiproliferative properties.
authors.affiliation: UFR biomédicale, Laboratoire de Pharmacochimie Moléculaire et Cellulaire, Université Paris Descartes, Paris, F-75006, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Montes
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Braud
authors.forename: Maria A
authors.initials: MA
authors.lastname: Miteva
authors.forename: Mary-Lorène
authors.initials: ML
authors.lastname: Goddard
authors.forename: Odile
authors.initials: O
authors.lastname: Mondésert
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Kolb
authors.forename: Marie-Priscille
authors.initials: MP
authors.lastname: Brun
authors.forename: Bernard
authors.initials: B
authors.lastname: Ducommun
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D015203:Reproducibility of Results; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D020687:cdc25 Phosphatases