Identification of inhibitor binding site in human sirtuin 2 using molecular docking and dynamics simulations.

Sugunadevi Sakkiah,Keun Woo Lee,Manian Rajesh Kumar,Mahreen Arooj,Soo Hyun Eom,Chandra Verma

doi:10.1371/journal.pone.0051429

Abstract

The ability to identify the site of a protein that can bind with high affinity to small, drug-like compounds has been an important goal in drug design. Sirtuin 2 (SIRT2), histone deacetylase protein family, plays a central role in the regulation of various pathways. Hence, identification of drug for SIRT2 has attracted great interest in the drug discovery community. To elucidate the molecular basis of the small molecules interactions to inhibit the SIRT2 function we employed the molecular docking, molecular dynamics simulations, and the molecular mechanism Poisson-Boltzmann/surface area (MM-PBSA) calculations. Five well know inhibitors such as suramin, mol-6, sirtinol, 67, and nf675 were selected to establish the nature of the binding mode of the inhibitors in the SIRT2 active site. The molecular docking and dynamics simulations results revealed that the hydrogen bonds between Arg97 and Gln167 are crucial to inhibit the function of SIRT2. In addition, the MM-PBSA calculations revealed that binding of inhibitors to SIRT2 is mainly driven by van der Waals/non-polar interactions. Although the five inhibitors are very different in structure, shape, and electrostatic potential, they are able to fit in the same binding pocket. These findings from this study provide insights to elucidate the binding pattern of SIRT2 inhibitors and help in the rational structure-based design of novel SIRT2 inhibitors with improved potency and better resistance profile.

Highlights

The Sir2 or sirtuin family of class III deaceatylases differs from class I and II histone deacetylases (HDACs) by their sequences and structure [1]
Seven NAD+-dependent HDAC proteins were recognized in mammalians, SIRT1-7 differs in the subcellular localization, substrate specificities, and functions
In order to gain the insight into the recognition between the Sirtuin 2 (SIRT2) and inhibitors, molecular docking simulations were done on the 3-D structure of SIRT2 since they represent the pharmacology target for the development of new drugs to treat various diseases

Summary

Introduction

The Sir (silence information regulator 2) or sirtuin family of class III deaceatylases differs from class I and II histone deacetylases (HDACs) by their sequences and structure [1]. Sirtuins are evolutionarily conserved NAD+-dependent protein deacetylases and adenosine diphosphate (ADP)-ribosylases. Sirtuin catalyze the deacetylation of lysine residues on histones and various proteins, resulting in a deacetylated product as nicotinamide, and O-acetyl-ADP-ribose [2,3,4,5]. The catalytic domain consists of a large typical Rossmann fold or the classic pyridine dinucleotide binding fold, and a small domain composed of residues from two insertions within the Rossman fold, one comprising a zinc-binding module that contains a structural zinc atom coordinated by 4 invariant cysteine’s, and the other forming a helical module that includes a flexible loop. The cofactor–binding pocket can be divided into 3 regions: A-Site: binding of adenine ribose moiety of NAD+, B-Site: Nicotinamide ribose binding moiety and C-Site: located deep inside the pocket and contains the catalytic center Fig. 1 [6]

Methods

Results

Conclusion