Molecular docking and dynamics simulation study of flavonoids as BET bromodomain inhibitors.

Bromodomains (BRDs) are the epigenetic proteins responsible for transcriptional regulation through its interaction with methylated or acetylated histone residues. The lysine residues of Bromodomain-1 (BD1) of Brd4 undergo ε-N-Acetylation posttranslational modifications to control transcription of genes. Due to its role in diverse cellular functions, Brd4 of bromodomain family, was considered as a prominent target for many diseases such as cancer, obesity, kidney disease, lung fibrosis, inflammatory diseases, etc. In this study, an attempt has been made to screen compounds from flavonoids and extended flavonoids libraries targeting acetylated lysine (KAc) binding site of BD1 of Brd4 using docking and molecular dynamics simulations. Two different docking programs AutoDock and Glide were used to compare their suitability for the receptor. Interestingly, in both the docking programs, the screened flavonoids have occupied the same binding pocket confirming the selection of active site. Further the MMGBSA binding free energy calculations and ADME analysis were carried out on screened compounds to establish their anti-cancerous properties. We have identified a flavonoid which shows docking and Glide e-model score comparatively much higher than those of already reported known inhibitors against Brd4. The protein-ligand complex with top-ranked flavonoid was used for dynamics simulation study for 50 ns in order to validate its stability inside the active site of Brd4 receptor. The results provide valuable information for structure-based drug design of Brd4 inhibitors.