Abstract
Bromodomain containing proteins recognize the level of histone acetylation and regulate epigenetically controlled processes like gene transcription and chromatin modification. The BET (bromodomain and extra-terminal) family proteins, which are transcriptional co-regulators, have been implicated in the pathogenesis of cancer, neurodegenerative disorders, and defects in embryonic stem cell differentiation. Inhibitors selectively targeting the BET bromodomains can pave the path for new drug discovery against several forms of major diseases. By a rational structure-based approach, we have identified a new inhibitor (NSC127133) of the second bromodomain (BD2) of the BET family protein BRD2 using the NCI Diversity Set III library. A high-resolution crystal structure of the BRD2-BD2 in complex with this compound and in apo- form is refined to 0.91 and 0.94 Å, respectively. The compound, which is a phenanthridinone derivative, binds well to the acetyl-lysine binding pocket of BD2 and displays significant hydrophobic and hydrophilic interactions. Moreover, the atomic resolution data obtained in this study allowed us to visualize certain structural features of BD2 which remained unobserved so far. We propose that the discovered compound may be a potential molecule to develop a new library for inhibiting the BRD2-BD2 function.
Highlights
The nucleosome is a primary component of chromatin, packing 147 base pair length of DNA around a histone octamer, leading to an organized and compact chromatin [1]
The PyMol program plugged with AudoDock Vina was used to visually check the predicted binding conformations for the selected conformations from the sorted list
The predicted 10 compounds possess ligand efficiency (LE) greater than 0.29 (S1 Table), and subsequently, these compounds were subjected to co-crystal structure analysis
Summary
The nucleosome is a primary component of chromatin, packing 147 base pair length of DNA around a histone octamer, leading to an organized and compact chromatin [1]. The post-translational modifications such as acetylation of lysine residues (Kac) on the histone tails and the recognition of acetylated-histone tails are a typical hallmark of transcription activation [2]. Bromodomains are known to be the epigenetic readers. They selectively recognize acetylated lysine residues on the histone tails, a key event in reading the post-translational modifications. BRD2 Bromodomain Inhibitor design, data collection and analysis, decision to publish, or preparation of the manuscript
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