Potential inhibitors of bromodomain-containing protein 4 (BRD4) against prostate cancer using molecular docking and network pharmacology

Abstract

Background: Bromodomain-containing protein 4 (BRD4) has emerged as a promising therapeutic target in prostate cancer (PCa). This chromatin reader protein, crucial for regulating gene expression through its bromodomains, plays a pivotal role in recognizing acetylated lysine residues on histones and recruiting RNA polymerase II. In the context of PCa, BRD4's overexpression and amplification are correlated with aggressive phenotypes, tumor progression, and the development of castration-resistant prostate cancer (CRPC), positioning BRD4 as a compelling target for therapeutic intervention.
Methods: The study conducted a thorough examination of protein and ligand interactions, focusing on 17 compounds. Ergosterol exhibited the most favorable binding affinity to the BRD4 receptor, and 2D visualizations provided detailed insights into dynamic interactions, revealing hydrogen bonds and key amino acid residues involved. Additionally, the research delved into network analyses, visualizing a network illustrating the interaction between bioactive components from marine sponges and their target receptors. Protein-protein interaction networks (PPINs) for prostate cancer disease and BRD4 were explored, highlighting the interconnectedness of proteins and shedding light on BRD4's potential roles in the broader context of PCa.
Results: The examination of 17 compounds revealed that ergosterol demonstrated the highest binding affinity to the BRD4 receptor. Detailed 2D visualizations unveiled the dynamic interactions, emphasizing specific hydrogen bonds and amino acid residues involved in the binding process. Network analyses depicted the intricate interactions between bioactive components and their target receptors, providing a comprehensive overview. PPINs for prostate cancer and BRD4 showcased the interconnectedness of proteins, elucidating potential roles of BRD4 beyond its primary function.
Conclusion: PCa BRD4 protein-ligand interactions were explored in this comprehensive study. Ergosterol is the most BRD4 receptor-affine of 17 ligands. Network analysis of marine sponge bioactive components and target receptors was also performed. Examining prostate cancer disease protein-protein interaction networks and BRD4 protein showed BRD4's complex role in PCa. Enrichment analysis revealed core target protein biological processes, molecular functions, cellular components, and signaling networks.