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In silico design and bioevaluation of selective benzotriazepine BRD 4 inhibitors with potent antiosteoclastogenic activity
Author(s) -
Deepak Vishwa,
Wang Binglin,
Koot Dwayne,
Kasonga Abe,
Stander Xiao Xing,
Coetzee Magdalena,
Stander Andre
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12930
Subject(s) - osteoclast , in silico , bromodomain , chemistry , acetylation , viability assay , docking (animal) , epigenetics , biochemistry , microbiology and biotechnology , pharmacology , in vitro , biology , gene , medicine , nursing
The bromodomain ( BRD ) and extra‐terminal domain ( BET ) protein family bind to acetylated histones on lysine residues and act as epigenetic readers. Recently, the role of this protein family in bone loss has been gaining attention. Earlier studies have reported that benzotriazepine (Bzt) derivatives could be effective inhibitors of BET proteins. In this study, using in silico tools we designed three Bzt analogs (W49, W51, and W52). By docking, molecular simulations, and chemiluminescent Alpha Screen binding assay, we show that the studied analogs were selective at inhibiting BRD 4 when compared to BRD 2. Furthermore, we tested the effectiveness of these analogs on osteoclast formation and function. Among the examined analogs, Bzt‐W49 and Bzt‐W52 were found to be the most potent inhibitors of osteoclastogenesis without cytotoxicity in murine RAW 264.7 osteoclast progenitors. Both the compounds also inhibited osteoclast formation without affecting cell viability in human CD 14+ monocytes. Moreover, owing to attenuated osteoclastogenesis, actin ring formation and bone resorptive function of osteoclasts were severely perturbed. In conclusion, these results suggest that the novel BRD 4‐selective Bzt analogs designed in this study could be explored further for developing therapeutics against bone loss diseases characterized by excessive osteoclast activity.