Cytosporone E analogues as BRD4 inhibitors for cancer treatment: molecular docking and molecular dynamic investigations

Abstract

Cancer is considered one of the worldwide life-threatening and leading causes of human mortality. In 2020, 19,292,789 cancer cases and 9,958,133 cancer deaths have been estimated worldwide. Therefore, efforts have been devoted to discover novel anticancer agents. Bromodomains have a vital role in the regulation of transcription. Many reports have shown that bromodomain-containing protein 4 (BRD4) is an important target for cancer therapeutics. In this study, several in silico approaches were utilized to discover new inhibitors against the BRD4 protein using the Schrodinger suite. A library of 27 cytosporone E derivatives was docked into the active site of the BRD4 protein. Docked ligands showed docking scores ranging between −11.289 to −3.992 Kcal/mol. Ligands 1–4 showed better binding affinities with docking scores ranging from −11.289 to −8.917 Kcal/mol compared to the reference ligand BI-2536 (−8.426 Kcal/mol). These ligands displayed favorable MM-GBSA free binding energy. Also, ligands 1–4 were subjected to molecular dynamics simulations for 100 ns to get insight into the ligand-binding stability. These compounds exhibited an average RMSD below 2.8 Å, indicating the stability of the compounds with BRD4 protein. Further, Moreover, ligands 1–3 displayed favorable AMDET properties (absorption, distribution, metabolism, excretion, and toxicity). These new compounds might be potential leads to combat cancer. Communicated by Ramaswamy H. Sarma