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Sequence Effects and Ligand Selectivity in Targeting Non‐Canonical DNA Structures
Author(s) -
Rodriguez Marc,
Kerwin Sean,
Dollison Lydia
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04745
Subject(s) - ligand (biochemistry) , selectivity , dna , chemistry , autodock , stereochemistry , molecule , dna replication , small molecule , docking (animal) , computational biology , combinatorial chemistry , gene , biology , in silico , biochemistry , receptor , organic chemistry , catalysis , medicine , nursing
G‐Quadruplex (G4) DNA is a DNA structure that can occur in G‐rich DNA sequences. These structures, which are compact and diverse, have been implicated in a wide range of processes including telomere maintenance, transcriptional control, and DNA replication and repair. In order to target specific G4 structures, and thus selectively affect these functions, improved small‐molecule ligands are required. We have carried out a docking study to explore the structural origins of ligand selectivity for different topological families of G4 structures. Using Autodock Vina, we have analyzed the G4 binding affinity, mode, and selectivity of previous reported and newly designed bis(quinolin‐3‐ylmethylene)‐based ligands towards hybrid and parallel stranded G‐quadruplex structures. Based on this analysis, we have embarked on the synthesis of one such novel bis(quinolin‐3‐ylmethylene)‐based ligand, which is predicted to be more selective for parallel‐stranded G4 structures. In addition, this ligand is predicted to be more readily taken up by cells compared to the parent bis(quinolin‐3‐ylmethylene)‐based ligands.