title: Rational identification of natural organic compounds to target the intermolecular interaction between Foxm and DNA in colorectal cancer.
abstract: 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.
authors.affiliation: Nursing Office, North Medical Sector, Linyi People's Hospital, Linyi 276003, China.
authors.forename: Chunling
authors.initials: C
authors.lastname: Dong
authors.affiliation: Department of Rheumatology, Linyi People's Hospital, Linyi 276003, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Yan
authors.affiliation: Linyi Municipal Health and Family Planning Commission, Linyi 276001, China.
authors.forename: Juxun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Linyi People's Hospital, Linyi 276003, China.
authors.forename: Hailian
authors.initials: H
authors.lastname: Mu
authors.affiliation: Department of Geratology, Linyi People's Hospital, Linyi 276003, China.
authors.forename: Shuli
authors.initials: S
authors.lastname: Wang
authors.affiliation: The People's Hospital of Linzi District, Zibo 2255400, China. Electronic address: gfch2008@163.com.
authors.forename: Fangchun
authors.initials: F
authors.lastname: Guo
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D055808:Drug Discovery; D000072278:Forkhead Box Protein M1 / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D004247:DNA
keywords: Chemotherapy; Colorectal cancer; Forkhead box M; Natural organic compound; Rational drug discovery