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.

journal_name

J Chem Inf Model

authors

Montes M,Braud E,Miteva MA,Goddard ML,Mondésert O,Kolb S,Brun MP,Ducommun B,Garbay C,Villoutreix BO

doi

10.1021/ci700313e

subject

Has Abstract

pub_date

2008-01-01 00:00:00

pages

157-65

issue

1

eissn

1549-9596

issn

1549-960X

journal_volume

48

pub_type

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