Flavonoids as Putative Epi-Modulators: Insight into Their Binding Mode with BRD4 Bromodomains Using Molecular Docking and Dynamics

Abstract

Flavonoids are widely recognized as natural polydrugs, given their anti-inflammatory, antioxidant, sedative, and antineoplastic activities. Recently, different studies showed that flavonoids have the potential to inhibit bromodomain and extraterminal (BET) bromodomains. Previous reports suggested that flavonoids bind between the Z and A loops of the bromodomain (ZA channel) due to their orientation and interactions with P86, V87, L92, L94, and N140. Herein, a comprehensive characterization of the binding modes of fisetin and the biflavonoid, amentoflavone, is discussed. To this end, both compounds were docked with BET bromodomain 4 (BRD4) using four docking programs. The results were post-processed with protein–ligand interaction fingerprints. To gain further insight into the binding mode of the two natural products, the docking results were further analyzed with molecular dynamics simulations. The results showed that amentoflavone makes numerous contacts in the ZA channel, as previously described for flavonoids and kinase inhibitors. It was also found that amentoflavone can potentially make contacts with non-canonical residues for BET inhibition. Most of these contacts were not observed with fisetin. Based on these results, amentoflavone was experimentally tested for BRD4 inhibition, showing activity in the micromolar range. This work may serve as the basis for scaffold optimization and the further characterization of flavonoids as BET inhibitors.

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“…The presence of the bulky glucuronic acid moiety in the quercetin-O-glucoside molecule would result in the loss of interaction and supports the lack of inhibition of the compound in our experiments. Our preliminary data highlight the usefulness of docking analyses to better understand the mode of action of PCs and will be confirmed by crystallization studies [61].…”

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“…The biflavonoid amentoflavone, found in Hypericum perforatum , Nandina domestica , Gingko biloba , and Biophytum sensitivum , was shown to dock into the N-acetyl-binding site of BRD4, making several contacts with the ZA channel and with non-canonical residues. Subsequent experiments confirmed the inhibition of BRD4 by amentoflavone in the micromolar range [ 102 ].…”

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“…In silico also called virtual screening of compound databases has been a very useful approach to identify hit compounds [30]. Compound databases from different sources such as synthetic libraries, natural product data sets [31], and even virtual libraries (where compounds are cherry-picked for synthesis and experimental testing) are screened regularly. To this end, two general approaches structure-based and ligand-based methods are employed.…”