TRAF2 and NCK-Interacting Kinase Inhibitors for Colorectal Cancer: In Vitro and Theoretical Validations.
Sherlin Rosita ArokiarajNargis Begum TajuddinKarthikeyan MuthusamyJohn Marshal JayarajManikandan AlagumuthuPublished in: ACS combinatorial science (2020)
TRAF2 and NCK-interacting kinase (TNIK) is a critical factor in colorectal cancer (CRC) proliferation mediated by Wnt signaling. We attempted to identify efficient TNIK inhibitors using computational high-throughput virtual screening (HTVS) from various drug banks and databases. By performing/on performing e-pharmacophore screening and molecular docking methods, from ∼700 000 molecules, compounds LC_222150, LC_112060, and LC_64796 were identified as potential leads, through molecular dynamics (MD) simulations and density functional theory (DFT). These top 3 structures were commercially procured, and their inhibitory activity was assessed in vitro. Significant TNIK inhibition was observed, with an average IC50 of 18.33 ± 0.75 nM. In terms of anticancer activity, the observed average relative % activity (RPA) of 90.28 ± 1.04 for these compounds compared well with doxorubicin (86.75 ± 1.45) as a standard. Compounds LC_222150, LC_112060, and LC_64796, therefore, warrant further evaluation in vivo to assess their CRC therapeutic effects.
Keyphrases
- molecular dynamics
- density functional theory
- molecular docking
- simultaneous determination
- high throughput
- mass spectrometry
- emergency department
- molecular dynamics simulations
- solid phase extraction
- signaling pathway
- drug delivery
- machine learning
- single cell
- human health
- electronic health record
- drug induced
- high resolution mass spectrometry