Pharmacoinformatic discovery of plant-derived BRD4 inhibitors as potential therapeutic agents for leukemia

Leukemia is a type of blood cancer that occurs when abnormal white blood cells grow too quickly. This uncontrolled growth begins in the bone marrow, where blood cells are produced. Leukemia remains a major health concern due to its high incidence and difficult prognosis. It is the most common type of cancer in children and ranks among the top 15 most prevalent cancers in adults, as reported by the World Health Organization. Several BRD4 inhibitors have shown promising potential as treatments for leukemia. These molecules function by blocking BRD4's interaction with acetylated histones, specifically targeting key amino acid residue ASN140. By disrupting this binding, they offer a potentially more effective therapeutic approach in combating leukemia. Current cancer treatments, such as chemotherapy and targeted therapies like JQ1, frequently come with side effects and toxicity, which highlights the need for safer alternatives. In our study, we explored plant-derived natural compounds that might offer anticancer benefits while being easier on the body. Using advanced techniques like pharmacophore-based virtual screening and ADMET analysis, we identify potential candidates. Molecular docking and dynamics simulations further revealed strong and stable interactions between BRD4 protein and these compounds. Notably, Calyxins C had the best interaction profile, with a docking score of -12.756 kcal/mol and a binding free energy of -85.32 kcal/mol. For Calyxins A, the binding free energy was -72.53 kcal/mol with a docking score of -10.132 kcal/mol, while for Deoxycalyxin A, it was -73.03 kcal/mol with a docking score of -10.162 kcal/mol. Our research indicates that these natural compounds, Calyxins C, Calyxins A, and Deoxyocalyxin A, exhibit higher stability and favorable interaction profiles, which could be effective and less toxic drug leads for leukemia treatment, paving the way for future experimental validation and clinical studies.