Research Article Molecular Docking Study Characterization of Rare Flavonoids at the Nac-Binding Site of the First Bromodomain of BRD4 (BRD4 BD1) Karthik Dhananjayan Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham University, AIMS Health Sciences Campus, Kochi, Kerala 682041, India Correspondence should be addressed to Karthik Dhananjayan; karthikdcology@gmail.com Received 27 September 2014; Revised 13 February 2015; Accepted 13 February 2015 Academic Editor: Daizo Yoshida Copyright © 2015 Karthik Dhananjayan. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. -N-Acetylation of lysine residues (Kac) is one of the most frequently occurring posttranslational modiications (PTMs) which control gene transcription and a vast array of diverse cellular functions. Bromodomains are epigenetic regulators involved in posttranslational modiication. In silico docking studies were carried out to evaluate the binding potential of selected rare lavonoids on to Nac binding site of BD1 domain of BRD4 BET family proteins. Rare lavonoids like 3-O-acetylpinobanksin, naringenin triacetate, and kaempferol tetraacetate were found to occupy the WPF shelf and at the same time they exhibited a better binding ainity with multiple crystal structures of irst bromodomain BRD4 (BRD4 BD1) when compared with the known inhibitors. 1. Introduction he recent discovery of promising small molecule inhibitors for a class of nonenzymatic chromatin regulators, the BET bromodomains, suggests that future drug discovery for epige- netic therapy will involve the modulation of protein-protein interactions and multiprotein complexes. Also, it is expected that target-based discovery strategies will be increasingly complemented by approaches based on chemical probes gen- erated by phenotypic or mechanistic cell based screening [1]. he bromodomain (BD) and extra terminal (BET) pro- teins, which comprise four members in human viz., BRD2, BRD3, BRD4, and the testis-speciic BRDT [2] with each containing two N-terminal Bromodomains (BD). BRD4 and BRD2 are key mediators of transcriptional elongation by recruiting the positive transcription elongation factor com- plex (P-TEFb). he P-TEFb core complex is composed of cyclin-dependent kinase-9 (CDK9) and its activator cyclin T. CDK9 phosphorylates the RNA polymerase II (RNAPII) C- terminal domain, a region that contains 52 heptad repeats. RNAPII undergoes sequential phosphorylation at Ser5 dur- ing promoter clearance and at Ser2 by P-TEFb at the start of elongation. It has been shown that BRD4 couples P-TEFb to acetylated chromatin through its BRDs. Interestingly, in contrast to other BRD containing proteins and transcription factors, BET proteins remain associated with condensed and hypoacetylated mitotic chromosomes [3] suggesting a role in epigenetic memory [4, 5]. Acetylation of lysine residues is a posttranslational modi- ication with broad relevance to cellular signaling and disease biology. he principal readers of -N-acetyl-lysine (Kac) marks are bromodomains (BRDs), which are a diverse family of evolutionary conserved protein-interaction modules. he conserved BRD fold contains a deep, largely hydrophobic acetyl-lysine binding site, which represents an attractive pocket for the development of small pharmaceutically active molecules [6]. he bromodomain-containing protein-4 (BRD4) is a class of transcriptional regulators whose members are present in animals, plants, and fungi [7]. he BET proteins typically have two tandem N-terminal bromodomains followed by an ET domain. As predicted by the presence of bromodomains, these proteins have been found to be associated with acety- lated chromatin. BET proteins are involved in diverse cellular phenomena such as meiosis, cell-cycle control, and homeosis and have been suggested to modulate chromatin structure Hindawi Publishing Corporation Journal of Cancer Research Volume 2015, Article ID 762716, 15 pages http://dx.doi.org/10.1155/2015/762716