Issue 93, 2015

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

Abstract

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.

Graphical abstract: 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

Supplementary files

Article information

Article type
Paper
Submitted
11 Jul 2015
Accepted
03 Sep 2015
First published
04 Sep 2015

RSC Adv., 2015,5, 76642-76650

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

K. G. Moghaddam and S. M. Hashemianzadeh, RSC Adv., 2015, 5, 76642 DOI: 10.1039/C5RA13615F

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