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

Area of Science:

• Biochemistry
• Drug Discovery
• Computational Chemistry

Background:

• Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator implicated in triple-negative breast cancer (TNBC).
• Selective inhibition of BRD4's homologous BD1/BD2 domains is challenging due to their structural similarity.
• Targeting BRD4 offers therapeutic potential for TNBC.

Purpose of the Study:

• To identify selective inhibitors targeting the BD1 and BD2 domains of BRD4.
• To elucidate the binding mechanisms of these inhibitors with BRD4 BD1/BD2.
• To overcome challenges in achieving domain-specific inhibition of BRD4.

Main Methods:

• Screening of potential inhibitors from Traditional Chinese herbal medicines (TCMs) using AutoDock vina.
• Molecular dynamics (MD) simulations to investigate inhibitor-protein interactions.
• Utilizing FL-411 as a reference inhibitor for experimental comparison.

Main Results:

• Inhibitors were found to stabilize BRD4 BD1/BD2 conformations.
• Enhanced hydrophobic and salt-bridge interactions were observed with inhibitors.
• Specific atomic interactions identified: FL-411 with E85 of BD1, miltirone with H437 of BD2, demonstrating selectivity.

Conclusions:

• Key structural determinants for BRD4 BD1/BD2 selectivity were identified.
• MD simulations validated the screening approach and corroborated experimental findings.
• Artificial intelligence drug discovery (AIDD) generated novel inhibitors with improved binding affinity.