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

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.

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).

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.

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

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.