title: Structural determinants of the alpha2 adrenoceptor subtype selectivity.
abstract: Alpha2-adrenergic receptor (α2-AR) subtypes, acting mainly on the central nervous and cardiovascular systems, represent important targets for drug design, confirmed by the high number of studies published so far. Presently, only a few α2-AR subtype selective compounds are known. Using homology modeling and ligand docking, the present study analyzes the similarities and differences between binding sites, and between extracellular loops of the three subtypes of α2-ARs. Several α2-AR subtype selective ligands were docked into the active sites of the three α2-AR subtypes, key interactions between ligands and receptors were mapped, and the predicted results were compared with the available experimental data. Binding site analysis reveals a strong identity between important amino acid residues in each receptor, the very few differences being the key toward modulating selectivity of α2-AR ligands. The observed differences between binding site residues provide an excellent starting point for virtual screening of chemical databases, in order to identify potentially selective ligands for α2-ARs.
authors: Computational Chemistry Department, Institute of Chemistry Timisoara, M. Viteazu 24, 300223, Romania. lili.ostopovici@acad-icht.tm.edu.ro
authors: Liliana
authors: L
authors: Ostopovici-Halip
authors: Ramona
authors: R
authors: Curpăn
authors: Maria
authors: M
authors: Mracec
authors: Cristian G
authors: CG
authors: Bologa
references: Eur J Pharmacol. 1989 Sep 22;168(3):381-6
references: 2573535
references: Science. 2008 Nov 21;322(5905):1211-7
references: 18832607
references: Brain Res. 1995 Mar 20;674(2):238-44
references: 7796102
references: J Mol Biol. 2004 Sep 10;342(2):571-83
references: 15327956
references: Methods Mol Biol. 2007;406:89-112
references: 18287689
references: Curr Protoc Bioinformatics. 2006 Oct;Chapter 5:Unit-5.6
references: 18428767
references: J Chem Inf Model. 2010 Apr 26;50(4):626-37
references: 20187660
references: Nucleic Acids Res. 2003 Jul 1;31(13):3503-6
references: 12824354
references: Naunyn Schmiedebergs Arch Pharmacol. 2001 Jul;364(1):27-32
references: 11485035
references: Nature. 1997 Sep 11;389(6647):203-6
references: 9296501
references: Neurochem Int. 2009 Nov;55(6):355-61
references: 19447153
references: J Mol Biol. 1993 Dec 5;234(3):779-815
references: 8254673
references: Curr Med Chem. 2006;13(14):1667-91
references: 16787212
references: Br J Pharmacol. 2007 Feb;150(4):391-402
references: 17220913
references: J Med Chem. 2007 Aug 9;50(16):3964-8
references: 17630725
references: Chem Rev. 2005 Sep;105(9):3297-351
references: 16159154
references: J Mol Biol. 2000 Sep 8;302(1):205-17
references: 10964570
references: Bioinformatics. 2003 Dec 12;19(18):2500-1
references: 14668246
references: Br J Pharmacol. 2007 Feb;150(4):381-2
references: 17220912
references: Adv Protein Chem. 2003;63:243-90
references: 12629973
references: Nature. 2008 May 15;453(7193):363-7
references: 18480818
references: Drug Discov Today. 2009 Jul;14(13-14):676-83
references: 19422931
references: J Comput Aided Mol Des. 2009 Nov;23(11):807-28
references: 19757091
references: Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16123-8
references: 17060607
references: Br J Pharmacol. 1990 Mar;99(3):560-4
references: 1970500
references: Mol Pharmacol. 1991 Aug;40(2):168-79
references: 1678850
references: Mol Endocrinol. 2003 Aug;17(8):1640-6
references: 12764077
references: Science. 2000 Aug 4;289(5480):739-45
references: 10926528
references: Science. 2007 Nov 23;318(5854):1258-65
references: 17962520
references: J Pharmacol Exp Ther. 1994 Dec;271(3):1558-65
references: 7996470
references: Curr Opin Drug Discov Devel. 2003 May;6(3):353-61
references: 12833668
references: Nucleic Acids Res. 2003 Jan 1;31(1):365-70
references: 12520024
references: Annu Rev Biophys Biomol Struct. 2002;31:443-84
references: 11988478
references: Nature. 2008 Jul 24;454(7203):486-91
references: 18594507
references: Nature. 2009 May 21;459(7245):356-63
references: 19458711
references: J Mol Biol. 1997 Sep 12;272(1):144-64
references: 9299344
references: J Pharmacol Exp Ther. 2000 Apr;293(1):1-7
references: 10734146
references: J Pharmacol Exp Ther. 1997 Apr;281(1):48-53
references: 9103479
references: Protein Sci. 2000 Sep;9(9):1753-73
references: 11045621
references: Trends Pharmacol Sci. 2008 Dec;29(12):616-25
references: 18838178
references: Pharmacol Ther. 1999 Nov;84(2):193-205
references: 10596906
references: Eur J Pharmacol. 1991 Sep 17;202(2):235-43
references: 1666366
references: J Med Chem. 2006 Nov 16;49(23):6789-801
references: 17154509