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Flavonoids as Putative Epi-Modulators: Insight into Their Binding Mode with BRD4 Bromodomains Using Molecular Docking
Fernando D Prieto-Martínez1, José L Medina-Franco2
1Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Avenida Universidad 3000, Mexico City 04510, Mexico. fprieto@comunidad.unam.mx.
Biomolecules
|July 26, 2018
Summary
Amentoflavone, a natural flavonoid, shows potential for inhibiting bromodomain and extraterminal (BET) bromodomains by interacting with the ZA channel of BRD4. This discovery opens avenues for developing novel BET inhibitors.
Area of Science:
- Biochemistry
- Pharmacology
- Medicinal Chemistry
Background:
- Flavonoids are natural compounds with diverse bioactivities, including anti-inflammatory and antineoplastic effects.
- Emerging research indicates flavonoids can inhibit bromodomain and extraterminal (BET) bromodomains, crucial epigenetic regulators.
- Previous studies suggest flavonoids bind to the ZA channel of bromodomains.
Purpose of the Study:
- To comprehensively characterize the binding modes of fisetin and amentoflavone with BET bromodomain 4 (BRD4).
- To evaluate the potential of amentoflavone as a BET inhibitor based on its binding interactions.
Main Methods:
- Molecular docking of fisetin and amentoflavone with BRD4 using four docking programs.
- Analysis of protein-ligand interactions using fingerprints.
- Molecular dynamics simulations to further investigate binding modes.
- Experimental validation of amentoflavone's BRD4 inhibitory activity.
Main Results:
- Amentoflavone demonstrated extensive contacts within the BRD4 ZA channel, consistent with known flavonoid and kinase inhibitor binding.
- Amentoflavone exhibited potential interactions with non-canonical residues, distinguishing it from fisetin.
- Experimental assays confirmed amentoflavone's inhibitory activity against BRD4 in the micromolar range.
Conclusions:
- Amentoflavone possesses significant binding interactions with BRD4, supporting its role as a BET inhibitor.
- The unique binding profile of amentoflavone offers a promising scaffold for developing novel BET inhibitors.
- This study provides a foundation for further optimization and characterization of flavonoids as BET inhibitors.
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