The Thiophene "Sigma-Hole" as a Concept for Preorganized, Specific Recognition of G⋅C Base Pairs in the DNA Minor Groove.
In spite of its importance in cell function, targeting DNA is under-represented in the design of small molecules. A barrier to progress in this area is the lack of a variety of modules that recognize G⋅C base pairs (bp) in DNA sequences. To overcome this barrier, an entirely new design concept for modules that can bind to mixed G⋅C and A⋅T sequences of DNA is reported herein. Because of their successes in biological applications, minor-groove-binding heterocyclic cations were selected as the platform for design. Binding to A⋅T sequences requires hydrogen-bond donors whereas recognition of the G-NH2requires an acceptor. The concept that we report herein uses pre-organized N-methylbenzimidazole (N-MeBI) thiophene modules for selective binding with mixed bp DNA sequences. The interaction between the thiophene sigma hole (positive electrostatic potential) and the electron-donor nitrogen of N-MeBI preorganizes the conformation for accepting an hydrogen bond from G-NH2. The compound-DNA interactions were evaluated with a powerful array of biophysical methods and the results show that N-MeBI-thiophene monomer compounds can strongly and selectively recognize single G⋅C bp sequences. Replacing the thiophene with other moieties significantly reduces binding affinity and specificity, as predicted by the design concept. These results show that the use of molecular features, such as sigma-holes, can lead to new approaches for small molecules in biomolecular interactions.
Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303-3083, USA.
Pu
P
Guo
Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303-3083, USA.
Ananya
A
Paul
Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303-3083, USA.
Arvind
A
Kumar
Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303-3083, USA.|Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
Abdelbasset A
AA
Farahat
Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303-3083, USA.
Dhiraj
D
Kumar
Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303-3083, USA.
Siming
S
Wang
Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303-3083, USA.
David W
DW
Boykin
Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303-3083, USA. wdw@gsu.edu.
W David
WD
Wilson
D020029:Base Pairing; D002412:Cations / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D055672:Static Electricity; D013876:Thiophenes / Q000737:chemistry*
D002412:Cations; D013876:Thiophenes; D004247:DNA
DNA minor groove; N-methylbenzimidazole thiophene; bioinformatics; biosensors; sigma-hole