The effect of amino substituents on the interactions of quinazolone derivatives with c-KIT G-quadruplex: insight from molecular dynamics simulation study for rational design of ligands

Stabilization of G-quadruplex structures in the oncogenic promoter regions with small molecules has attracted considerable attention as a promising target for cancer therapy. To discover such small molecules, understanding the nature of interactions between the ligand and G-quadruplex is of paramoun...

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Bibliographic Details
Published in:RSC advances 2015-01, Vol.5 (93), p.76642-76650
Main Authors: Moghaddam, Kiana Gholamjani, Hashemianzadeh, Seyed Majid
Format: Article
Language:English
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Summary:Stabilization of G-quadruplex structures in the oncogenic promoter regions with small molecules has attracted considerable attention as a promising target for cancer therapy. To discover such small molecules, understanding the nature of interactions between the ligand and G-quadruplex is of paramount importance. To precisely investigate how these interactions can be influenced by varying different substituents, binding interactions of some quinazolone derivatives (QDs) with c-KIT G-quadruplex were studied by molecular dynamics (MD) simulation. The results revealed that the QD–NH–CO– arrangement in quinazolone derivatives improve binding affinity toward c-KIT G-quadruplex and the amino substituents play a crucial role in hydrogen bond formation and electrostatic interactions with the phosphate backbone of the G-quadruplex. We also proposed a new derivative of quinazolone ( 7k ) with a terminal amino substituent instead of a 3-phenyl group. The binding free energy analysis suggested that this derivative stabilizes the c-KIT G-quadruplex much better than other derivatives. Furthermore, the calculated changes in solvent-accessible surface area (ΔSASA) were consistent with the binding free energy calculations. Our studies provide insight into the effect of different substituents on binding interactions between the ligand and G-quadruplex which can pave the way to rational ligand design.
ISSN:2046-2069
2046-2069
DOI:10.1039/C5RA13615F