title: Identification of novel FAK and S6K1 dual inhibitors from natural compounds via ADMET screening and molecular docking.
abstract: Focal adhesion kinase (FAK) and human p70 ribosomal S6 kinase (S6K1) are non-receptor protein tyrosine plays a vital role in cell signaling pathways, such as cell proliferation, survival, and migration. In this study, the 3D structure of FAK (PDB ID: 2AL6) and S6K1 (3A60) were chosen for docking 60 natural compounds attempted to identify novel and specific inhibitors from them. The 30 selected molecules with high scores were further analyzed using DSSTox tools and DS 3.5 ADMET software. Based on a high docking score and energy interaction, 3 of the 9 candidate compounds, neferine B, neferine A, and antroquinonol D, were identified and the inhibitory activity of these compounds were subsequently validated in the C6 glioma cell line. All three selected compounds show potential effects on cell viability by MTT assay. Neferine B, neferine A, and antroquinonol D showed an IC50 value of 10-, 12-, and 16-μM, respectively. Moreover, these compounds decreased the p-FAk and p-S6k1 proteins in a dose-dependent manner. The results of best docked neferine B, neferine A, and antroquinonol D have the potential for further development as a supplement to treat tumorigenesis and metastasis.
authors.affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan.
authors.forename: Varadharajan
authors.initials: V
authors.lastname: Thiyagarajan
authors.affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan.
authors.forename: Shin-Hung
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan.
authors.forename: Yu-Chuan
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan. Electronic address: cfweng@mail.ndhu.edu.tw.
authors.forename: Ching-Feng
authors.initials: CF
authors.lastname: Weng
mesh_terms: D000818:Animals; D001688:Biological Products / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014584:User-Computer Interface
chemical_list: D001688:Biological Products; D047428:Protein Kinase Inhibitors; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019893:Ribosomal Protein S6 Kinases
keywords: ADMET; FAK; Molecular docking; S6K1; Virtual screening