The oncogenic transcription factor forkhead box M (Foxm) is overexpressed in human colorectal cancer (CRC). Targeting the protein interaction with its cognate DNA has been established as an attractive approach to anti-CRC chemotherapy. State-of-the-art molecular dynamics (MD) simulations revealed that the Foxm adopts considerably different conformations to interact with and without its DNA partner; the holo conformation is tightly packed as a typical globulin configuration, whereas the apo form is locally unstructured that exhibits intrinsic disorder in DNA recognition helix, indicating that DNA binding can help the Foxm refolding. With this finding, the MD equilibrium structure of DNA-free Foxm was utilized to perform molecular docking virtual screening against a natural organic compound library. Consequently, six hit compounds were identified as potential small-molecule mediators of Foxm-DNA interaction; their binding affinities (KD) to Foxm DNA-binding domain were then determined to range between 3.8 and 230μM by using isothermal titration calorimetry. These compounds were suggested to recognize and stabilize the apo conformation of Foxm, thus shifting the binding reaction equilibrium of Foxm from DNA-bound to DNA-free states to disrupt the formation of Foxm-DNA adduct.
Keywords: Chemotherapy; Colorectal cancer; Forkhead box M; Natural organic compound; Rational drug discovery.
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