Identification of novel FAK and S6K1 dual inhibitors from natural compounds via ADMET screening and molecular docking

Varadharajan Thiyagarajan; Shin-Hung Lin; Yu-Chuan Chang; Ching-Feng Weng

doi:10.1016/j.biopha.2016.02.020

Identification of novel FAK and S6K1 dual inhibitors from natural compounds via ADMET screening and molecular docking

Biomed Pharmacother. 2016 May:80:52-62. doi: 10.1016/j.biopha.2016.02.020. Epub 2016 Mar 14.

Authors

Varadharajan Thiyagarajan¹, Shin-Hung Lin¹, Yu-Chuan Chang¹, Ching-Feng Weng²

Affiliations

¹ Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan.
² Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan. Electronic address: cfweng@mail.ndhu.edu.tw.

PMID: 27133039
DOI: 10.1016/j.biopha.2016.02.020

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.

Keywords: ADMET; FAK; Molecular docking; S6K1; Virtual screening.

MeSH terms

Animals
Biological Products / analysis*
Biological Products / chemistry
Biological Products / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor*
Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*
Focal Adhesion Protein-Tyrosine Kinases / metabolism
High-Throughput Screening Assays
Humans
Hydrogen Bonding
Molecular Docking Simulation*
Protein Kinase Inhibitors / analysis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Rats
Ribosomal Protein S6 Kinases / antagonists & inhibitors*
Ribosomal Protein S6 Kinases / metabolism
User-Computer Interface

Substances

Biological Products
Protein Kinase Inhibitors
Focal Adhesion Protein-Tyrosine Kinases
Ribosomal Protein S6 Kinases