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Small molecule binders recognize DNA microstructural variations via an induced fit mechanism
E Kathleen Carter1, Sarah Laughlin-Toth, Thomas Dodd
1Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA. iivanov@gsu.edu wdw@gsu.edu.
Physical Chemistry Chemical Physics : PCCP
|January 11, 2019
Summary
Medicinal chemists aim to regulate gene expression by designing small molecules that bind DNA. This study analyzes a synthetic binder, revealing structural factors crucial for sequence-specific DNA targeting and therapeutic applications in transcription regulation.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Drug Discovery
Background:
- Targeting protein-nucleic acid interactions is key for gene expression regulation.
- Transcription factors are challenging drug targets due to lack of suitable binding sites for small molecules.
Purpose of the Study:
- Design small molecules for sequence-specific DNA binding to modulate transcription factor association.
- Develop compounds targeting G/C base pairs via allosteric mechanisms for therapeutic applications.
Main Methods:
- Utilized long timescale molecular dynamics simulations.
- Analyzed the structural aspects of a synthetic minor groove binder-DNA complex.
- Investigated the relationship between binding affinity and structural factors.
Main Results:
- Demonstrated sequence-specific DNA association of the synthetic minor groove binder.
- Identified key structural factors contributing to binding selectivity.
- Provided insights into optimizing synthetic small molecules for DNA targeting.
Conclusions:
- Established a framework for rational design of selective DNA binders.
- Aimed at improving site-specific DNA targeting for therapeutic transcription regulation.
- Highlighted the potential of synthetic small molecules in medicinal chemistry.
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