Computational discovery of BRD4 inhibitors for neuroblastoma therapy using pharmacophore screening and molecular simulations

BRD4 ("Bromodomain-containing protein 4"), a recognized gene regulator, is an attractive target for therapeutic development, particularly for the management of neuroblastoma. An integrated pharmacoinformatic strategy for the development of new BRD4 inhibitors is examined in this research. Pharmacophores were used to digitally screen five databases, and the current study aims to determine the best binding modes by docking the screened hits to the BRD4 active site. Using the BRD4 protein co-crystal ligand (73B) (PDB ID: 4BJX) as a template, pharmacophore hypotheses were produced. Five databases were subjected to a pharmacophore-based virtual screening process, and 1089 hits that satisfied the screening requirements were selected for docking against the BRD4 receptor by using the SP module of the Glide tool. The top ten docked compounds with the highest binding affinities, ranging from - 9.623 to - 8.894 kcal/mol, were selected. Further, the biological activity and ADMET analysis revealed that the selected compounds have values that fall in the acceptable range. The protein-ligand complexes' stability was verified by performing molecular dynamics (MD) simulations of the binding positions of the top two compounds against the BRD4 receptor. The stability and binding free energies of the compounds indicate that these compounds may function as lead compounds to affect the biological activity of BRD4 in the in vitro studies.