Prospective use of molecular field points in ligand-based virtual screening: efficient identification of new reversible Cdc25 inhibitors

A series of novel reversible inhibitors of the dual-specificity phosphatase Cdc25 was discovered using a two-stage molecular field-based similarity analysis. This method compares molecules on the basis of electrostatic and steric features, rather than their underlying structures, facilitating scaffold-hopping to new chemotypes. In this prospective study, a field point pharmacophore model was generated from three structurally diverse, reversible Cdc25 inhibitors and used in field-based virtual screening of 3.7 million commercially available compounds. Seven thiazoles, from the small set of 35 compounds selected for testing, showed reversible inhibition of activity at all three isoforms of Cdc25 (Cdc25A, B and C) at micromolar concentrations. The new series are not structurally related to the initial three starting points, but share their biological properties. Substructure searching rapidly identified additional thiazoles with modest (10-fold) increases in activity equivalent to those of the initial three starting points. This study demonstrates the effectiveness of this ligand-based method to both define a pharmacophore and effect virtual screening resulting in rapid and efficient identification of chemical starting points for development of novel therapeutic agents.