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Allosteric, chiral-selective drug binding to DNA
1Department of Biochemistry, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA.
Summary
The anticancer drug enantiomer (-)-daunorubicin (WP900) selectively binds to left-handed DNA, unlike its counterpart (+)-daunorubicin which binds to right-handed DNA. This chiral selectivity offers new strategies for designing anticancer drugs targeting specific DNA forms.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Biophysics
Background:
- Daunorubicin is an established anticancer drug.
- DNA exists in right-handed (B-DNA) and left-handed (Z-DNA) conformations.
- Chiral molecules can exhibit enantioselective interactions with biological targets.
Purpose of the Study:
- To investigate the DNA binding properties of (-)-daunorubicin (WP900), an enantiomer of (+)-daunorubicin.
- To determine the chiral selectivity of WP900 and (+)-daunorubicin towards different DNA conformations.
- To explore the potential of WP900 as a targeted anticancer agent.
Main Methods:
- Equilibrium dialysis
- Fluorescence spectroscopy
- Circular dichroism
- Molecular dynamics simulations
Main Results:
- (-)-Daunorubicin (WP900) selectively binds to left-handed DNA, while (+)-daunorubicin binds to right-handed DNA.
- Both enantiomers act as allosteric effectors, altering DNA conformation.
- (+)-Daunorubicin converts left-handed DNA to a right-handed form, and WP900 converts right-handed DNA to a left-handed form.
- Molecular dynamics confirmed a feasible model for WP900 intercalation into left-handed DNA.
- Chiral selectivity for DNA binding is significantly higher than for chiral metal complexes.
Conclusions:
- The daunorubicin enantiomeric pair exhibits high chiral selectivity in DNA binding.
- WP900 demonstrates a strong preference for left-handed DNA.
- These findings pave the way for designing novel anticancer drugs that specifically target left-handed DNA structures.