Molecular Docking Study Characterization of Rare Flavonoids at the Nac-Binding Site of the First Bromodomain of BRD4 (BRD4 BD1)

Karthik Dhananjayan

doi:10.1155/2015/762716

Abstract

ε-N-Acetylation of lysine residues (Kac) is one of the most frequently occurring posttranslational modifications (PTMs) which control gene transcription and a vast array of diverse cellular functions. Bromodomains are epigenetic regulators involved in posttranslational modification. In silico docking studies were carried out to evaluate the binding potential of selected rare flavonoids on to Nac binding site of BD1 domain of BRD4 BET family proteins. Rare flavonoids 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 affinity with multiple crystal structures of first bromodomain BRD4 (BRD4 BD1) when compared with the known inhibitors.

Highlights

The recent discovery of promising small molecule inhibitors for a class of nonenzymatic chromatin regulators, the BET bromodomains, suggests that future drug discovery for epigenetic therapy will involve the modulation of protein-protein interactions and multiprotein complexes
The P-TEFb core complex is composed of cyclin-dependent kinase-9 (CDK9) and its activator cyclin T
Multiple crystal structures of first bromodomain (BD1) of bromodomain-containing protein-4 (BRD4) BET family with different resolutions was downloaded from RCSB protein data bank and investigating ligands with lowest binding energy was re-evaluated on different crystal structures

Summary

Introduction

The recent discovery of promising small molecule inhibitors for a class of nonenzymatic chromatin regulators, the BET bromodomains, suggests that future drug discovery for epigenetic therapy will involve the modulation of protein-protein interactions and multiprotein complexes. The principal readers of ε-N-acetyl-lysine (Kac) marks are bromodomains (BRDs), which are a diverse family of evolutionary conserved protein-interaction modules. GSK525762 binds to the acetylated lysine recognition motifs on the bromodomain of BET proteins, thereby preventing the interaction between the BET proteins and acetylated histone peptides This disrupts chromatin remodeling and gene expression. On this basis, some acetyl forms of flavonoids were selected and their binding affinity was analyzed. Multiple crystal structures of first bromodomain (BD1) of BRD4 BET family with different resolutions was downloaded from RCSB protein data bank and investigating ligands (rare flavonoids) with lowest binding energy was re-evaluated on different crystal structures

Materials and Methods

Docking Methodology

Results and Discussion

C18 Met105