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Molecular recognition of a carboxy pyridostatin toward G‐quadruplex structures: Why does it prefer RNA ?
Author(s) -
Rocca Roberta,
Talarico Carmine,
Moraca Federica,
Costa Giosuè,
Romeo Isabella,
Ortuso Francesco,
Alcaro Stefano,
Artese Anna
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13015
Subject(s) - g quadruplex , rational design , rna , chemistry , telomere , dna , small molecule , molecular dynamics , selectivity , stereochemistry , in silico , binding selectivity , solvation , docking (animal) , molecular model , molecule , mode of action , binding site , biophysics , biochemistry , biology , computational chemistry , gene , genetics , medicine , nursing , organic chemistry , catalysis
The pyridostatin ( PDS ) represents the lead compound of a family of G‐quadruplex (G4) stabilizing synthetic small molecules based on a N,N ′‐bis(quinolinyl)pyridine‐2,6‐dicarboxamide scaffold. Its mechanism of action involves the induction of telomere dysfunction by competing for binding with telomere‐associated proteins, such as human POT 1. Recently, through a template‐directed “in situ ” click chemistry approach, a PDS derivative, the carboxypyridostatin ( c PDS ), was discovered. It has the peculiarity to exhibit high molecular specificity for RNA over DNA G4, while PDS is a good generic RNA and DNA G4‐interacting small molecule. Structural data on the binding modes of these compounds are not available, and the selectivity mode of c PDS toward TERRA G4 is unknown too. Therefore, this work is aimed at rationalizing the selectivity of c PDS versus TERRA G4 by means of molecular dynamics and docking simulations, coupled to better understand the binding mode of these compounds to telomeric G4 structures. The comprehensive analysis of cPDS binding mode and its conformational behavior demonstrates the importance of the ligand conformation properties coupled with a remarkable solvation contribution. This work is expected to provide valuable clues for further rational design of novel and selective TERRA G4 binders.