Premium
Docking on the DNA G‐quadruplex: A molecular electrostatic potential study
Author(s) -
MondragónSánchez Juan Antonio,
Santamaria Ruben,
GarduñoJuárez Ramón
Publication year - 2011
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.21634
Subject(s) - chemistry , nucleic acid , stacking , dna , g quadruplex , density functional theory , molecular orbital , computational chemistry , docking (animal) , stereochemistry , molecule , biochemistry , organic chemistry , medicine , nursing
Abstract The G‐quadruplexes are four‐stranded nucleic acid structures with guanine‐rich sequences that play important biological roles in, for example, regulating telomerase association and activity. Recent evidence supports the hypothesis that the telomeric G‐quadruplex DNA represents a target of novel anticancer drug medication. In this work, we present results of the molecular electrostatic potential (MEP), together with the HOMO and LUMO frontier orbitals, which are physical quantities of concern in the docking of compounds on the G‐quadruplex. The calculations are performed in the frame of density functional theory at the B88LYP/6‐31G* level of theory. Additional functionals that introduce dispersion effects were also taken into consideration. The MEP potential and electron density of the frontier molecular orbitals of the G‐quadruplex exhibit topological deformations due to the coiled conformation of the compound when they are compared with the MEP and corresponding electron density of a DNA duplex with similar nucleic acid composition. The electrostatic active zone of the G‐quadruplex is localized on the top part of the quadruplex structure where the MEP acquires the most negative values. Additional computations on a set of three daunomycins, a common anticancer drug for duplex DNA, indicate an electrostatic fastening between the quadruplex and the set of daunomycins. In this regard, the G‐quadruplex electrostatic interactions favor the stacking of ligands. Finally, some implications on molecular drug design are briefly discussed. © 2011 Wiley Periodicals, Inc. Biopolymers 95: 641–650, 2011.