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

Abstract

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 (K) 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.

Mapping the ligand binding landscape

“…There are currently 61 known distinct human bromodomains that are contained in 46 different proteins [27]. Bromodomains have been of intense therapeutic interest in recent years [28][29][30][31][32][33][34][35][36][37][38][39], as bromodomain inhibitors have been proposed as treatments for cancer, diabetes and inflammation. Much attention has been given to the bromodomain and extraterminal (BET) family, including Brd4 for which the first inhibitor was discovered in 2010 [40].…”

Flavonoids as Putative epi-modulators: Insights into their Binding Mode with BRD4 Bromodomain using Molecular Docking and Dynamics.

“…Fisetin on the other hand, shows more contacts with residues Met105 and Met132. Previous reports of docking indicate that flavonoids have a notable preference towards these residues [26], in the case of fisetin, affinity for Cys136 has also been observed [46]. This hints to flavonoids having a significant affinity towards different residues beyond the Ac-pocket, while their aromatic character gives them selectivity for the WPF shelf.…”

“…Bromodomain inhibitors may be classified on two broad categories: Kac mimicking and non-mimicking, the former being the most prominent [55]. Flavonoids belong to this category as their carbonyl groups are their main anchor towards Asn140 and Tyr97 [46]. Nonetheless, as shown on Figure 4, these interactions are not as populated as it might be expected.…”

“…Since amentoflavone and fisetin have been identified as putative ligands of BRD4 in two independent studies [46,47], a comprehensive characterization of the putative binding profile of both flavonoids with BRD4 is presented herein. The binding profile was carried out with consensus docking and molecular dynamics.…”

Untitled

“…Out of these 177 protein sequences, 43 had DO term while 13 (out of these 43 sequences) were having homology with human proteome. Remaining 30 hypothetical uncharacterized protein sequences were observed which had DO term but were not homologous with human proteome 26,27 . Thus, the 30 uncharacterized proteins may be used as putative drug target for M. leprae.…”