Discovery of new inhibitors of Cdc25B phosphatases by molecular docking-based virtual screening.

• Cdc25 phosphatases are key regulators of the eukaryotic cell cycle. • Cdc25A and b are overexpressed in many cancers, being key targets for drug discovery. • Molecular docking-based virtual screening was used to discover Cdc25B inhibitors. • Y11 and Y19 displayed inhibitory activity to Cdc25B. • Y19 showed anti-growth activity against the A549 cancer cell. Cell division cycle 25 (Cdc25) phosphatases play key roles in both normal and abnormal cell proliferation, which represent attractive drug targets for anticancer therapies. To discover subtype selective Cdc25B inhibitors with diverse scaffolds, a molecular docking-based virtual screening approach was performed by docking >3.8 million compounds into the Cdc25B catalytic site. An initial subset of 19 compounds was selected and assayed, and most compounds showed Cdc25B enzyme inhibition activity at 200 μM. Among these, 2 structurally diverse compounds Y11 (IC 50 = 156.30 ± 7.19 μM) and Y19 (IC 50 = 118.85 ± 12.07 μM) displayed micromolar inhibitory activity and subtype selectivity to Cdc25B phosphatases. Y19 was found to have anti-growth activity against the A549 cancer cell at micromolar profile. Additionally, molecular dynamics (MD) simulations and binding free energy calculations (MM/GBSA) were done to elucidate the binding mechanisms. The predicated ADMET properties suggested that Y11 and Y19 could serve as starting points for development of subtype selective Cdc25B phosphatases inhibitors. [ABSTRACT FROM AUTHOR]