title: Molecular modelling studies of sirtuin 2 inhibitors using three-dimensional structure-activity relationship analysis and molecular dynamics simulations.
abstract: Sirtuin 2 (SIRT2) is a nicotinamide-adenine-dinucleotide-dependent histone deacetylase that plays a vital role in various biological processes related to DNA regulation, metabolism, and longevity. Recent studies on SIRT2 have indicated its therapeutic potential for neurodegenerative diseases such as Parkinson's disease. In this study, a series of SIRT2 inhibitors with a 2-anilinobenzamide core was analysed using a combination of molecular modelling techniques. A three-dimensional structure-activity relationship (3D-QSAR) model adopting a comparative molecular field analysis (CoMFA) method with a non-cross-validated correlation coefficient R(2) = 0.992 (for training set) and a correlation coefficient Rtest(2) = 0.804 (for test set) was generated to determine the structural requirements for inhibitory activity. Furthermore, we employed molecular dynamics (MD) simulations and the molecular mechanics/generalized Born surface area (MM/GBSA) method to compare the binding modes of a potent and selective compound interacting with SIRT1, SIRT2, and SIRT3 and also their binding free energies to shed light on the selectivity of the footing of structural and energetic investigations. The steric and electrostatic contour maps from the 3D-QSAR analysis identified several key interactions also observed in the MD simulations. According to these results, we provide guidelines for developing novel potent and selective SIRT2 inhibitors.
authors.affiliation: Department of Life Sciences, National University of Kaohsiung, 700, Kaohsiung University Road, Nan-Tzu District 811, Kaohsiung, Taiwan. cnyang@nuk.edu.tw.
authors.forename: Yu-Chung
authors.initials: YC
authors.lastname: Chuang
authors.forename: Ching-Hsun
authors.initials: CH
authors.lastname: Chang
authors.forename: Jen-Tai
authors.initials: JT
authors.lastname: Lin
authors.forename: Chia-Ning
authors.initials: CN
authors.lastname: Yang
mesh_terms: D001665:Binding Sites; D004789:Enzyme Activation; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D054852:Small Molecule Libraries
chemical_list: D056572:Histone Deacetylase Inhibitors; D054852:Small Molecule Libraries; D056565:Sirtuin 2