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image of Exploring the Selective Potential Inhibitors for Homologous Protein BD1/BD2 with MD and AIDD Methods

Abstract

Introduction

The study aims to explore selective potential inhibitors for the homologous BD1/BD2 domains of bromodomain-containing protein 4 (BRD4) and uncover the binding mechanisms between these inhibitors and BD1/BD2. Given BRD4's role as an epigenetic regulator and its potential in treating triple-negative breast cancer (TNBC), overcoming the challenge of domain-specific inhibition due to the structural similarity of BD1 and BD2 is crucial.

Methods

For comparison with experimental research, FL-411 was selected as a novel inhibitor for BD1/BD2. The AutoDock vina method was employed to screen potential lead compounds of BD1/BD2 from Traditional Chinese herbal medicines (TCMs) for nervous diseases. Molecular dynamics (MD) simulations were conducted to investigate the interaction mechanisms between BD1/BD2 and potential inhibitors (miltirone/FL-411).

Results

The analysis shows that the inhibitors stabilize the conformation of BD1/BD2 and enhance their hydrophobic and salt-bridge interactions. Notably, atomic interaction studies reveal that the oxygen atom of FL-411 binds with E85 of BD1, while the 1,1-Dimethylcyclohexane group of miltirone binds with H437 of BD2, indicating the selective characteristics of these potential inhibitors.

Discussion

The study reveals key structural determinants for BD1/BD2 selectivity, addressing a major challenge in BRD4-targeted drug design. MD simulations support the experimental data, validating the screening approach.

Conclusion

Based on conformational characters of FL-411/miltirone and atomic interaction mechanism of BD1/BD2 and inhibitors, the potential inhibitors with a new skeleton and lower binding energy were generated with artificial intelligence drug discovery (AIDD) methods.

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2025-12-05

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Exploring the Selective Potential Inhibitors for Homologous Protein BD1/BD2 with MD and AIDD Methods
Bentham Science Publishers ; https://doi.org/10.2174/0115734099386097250922062749
/content/journals/cad/10.2174/0115734099386097250922062749
/content/journals/cad/10.2174/0115734099386097250922062749
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  • Article Type:     Research Article
Keywords: molecular dynamics simulation ; atomic interaction mechanism ; AIDD method ; TCMs ; homologous protein BD1/BD2 ; potential inhibitors

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