title: Identification of inhibitor binding site in human sirtuin 2 using molecular docking and dynamics simulations.
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.
authors: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea.
authors: Sugunadevi
authors: S
authors: Sakkiah
authors: Mahreen
authors: M
authors: Arooj
authors: Manian Rajesh
authors: MR
authors: Kumar
authors: Soo Hyun
authors: SH
authors: Eom
authors: Keun Woo
authors: KW
authors: Lee
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D055808:Drug Discovery; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000648:ultrastructure; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D056572:Histone Deacetylase Inhibitors; D056565:Sirtuin 2
references: J Med Chem. 2008 Mar 13;51(5):1203-13
references: 18269226
references: Science. 2004 Jul 16;305(5682):390-2
references: 15205477
references: Chem Biol Drug Des. 2012 Aug;80(2):315-27
references: 22564257
references: Cell Metab. 2005 Aug;2(2):105-17
references: 16098828
references: Genes Dev. 1999 Oct 1;13(19):2570-80
references: 10521401
references: Nature. 2004 Jun 17;429(6993):771-6
references: 15175761
references: Science. 2004 Aug 13;305(5686):1010-3
references: 15310905
references: Biochem Biophys Res Commun. 2003 Sep 26;309(3):558-66
references: 12963026
references: Cancer Invest. 2005;23(3):264-73
references: 15948296
references: Mol Cell Biol. 2002 Nov;22(22):8056-66
references: 12391171
references: EMBO J. 2001 Mar 15;20(6):1353-62
references: 11250901
references: Bioorg Med Chem Lett. 2012 Apr 15;22(8):2789-93
references: 22446090
references: Science. 2002 Dec 20;298(5602):2390-2
references: 12493915
references: EMBO J. 2002 Dec 16;21(24):6820-31
references: 12486003
references: Nature. 2003 Sep 11;425(6954):191-6
references: 12939617
references: EMBO J. 1999 May 4;18(9):2580-92
references: 10228170
references: Science. 2004 Mar 26;303(5666):2011-5
references: 14976264
references: Annu Rev Biochem. 2006;75:435-65
references: 16756498
references: Cell. 1989 Mar 10;56(5):771-6
references: 2647300
references: Nat Struct Biol. 2001 Jul;8(7):621-5
references: 11427894
references: Cell. 2001 Oct 19;107(2):149-59
references: 11672523
references: J Biomol Struct Dyn. 2012;30(3):235-54
references: 22694102
references: Science. 2007 Jul 27;317(5837):516-9
references: 17588900
references: Cell Mol Life Sci. 2010 Sep;67(18):3073-87
references: 20680393
references: Oncogene. 2009 Feb 12;28(6):781-91
references: 19060927
references: Biochem Biophys Res Commun. 2000 Jul 5;273(2):793-8
references: 10873683
references: Nature. 2003 May 8;423(6936):181-5
references: 12736687
references: Aging Cell. 2007 Aug;6(4):505-14
references: 17521387
references: Genes Dev. 2006 Nov 1;20(21):2913-21
references: 17079682
references: Cell Metab. 2008 Feb;7(2):104-12
references: 18249170
references: Genes Dev. 1997 Jan 15;11(2):241-54
references: 9009206
references: Biochemistry. 2009 Apr 7;48(13):2878-90
references: 19220062
references: J Med Chem. 2004 Dec 2;47(25):6292-8
references: 15566299
references: Nature. 2003 Jan 16;421(6920):230
references: 12529632
references: Nature. 2001 Mar 8;410(6825):227-30
references: 11242085
references: Cell. 2004 Feb 20;116(4):551-63
references: 14980222