In Silico Screening and Binding Characterization of Small Molecules toward a G-Quadruplex Structure Formed in the Promoter Region of c-MYC Oncogene

ACS Omega
Jyotsna BhatSubhrangsu Chatterjee

Abstract

Overexpression of c-MYC oncogene is associated with cancer pathology. Expression of c-MYC is regulated by the G-quadruplex structure formed in the G-rich segment of nuclease hypersensitive element (NHE III1), that is, "Pu27", which is localized in the promoter region. Ligand-induced stabilization of the Pu27 structure has been identified as a novel target for cancer therapeutics. Here, we have explored the library of synthetic compounds against the predefined binding site of Pu27. Three compounds were selected based on the docking analyses; they were further scrutinized using all atom molecular dynamics simulations in an explicit water model. Simulated trajectories were scrutinized for conformational stability and ligand binding free energy estimation; essential dynamic behavior was determined using principal component analysis. One of the molecules, "TPP (1-(3-(4-(1,2,3-thiadiazol-4-yl)phenoxy)-2-hydroxypropyl)-4-carbamoylpiperidinium)", with the best results was considered for further evaluation. The theoretical observations are supported well by biophysical analysis using circular dichroism, isothermal titration calorimetry, and high-resolution NMR spectroscopy indicating association of TPP with Pu27. The in vitro studies we...Continue Reading

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Methods Mentioned

BETA
in silico methods
circular
isothermal titration calorimetry
NMR
Flow Cytometry
Assay
Chemical shift
FACS
PCR
transfection

Software Mentioned

OligoAnalyser
Origin
PyMOL
TopspinTMv3
CPPTRAJ
molsurf
Maestro
PCAzip
MMGBSA
AMBER

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