title: Molecular mechanism of serotonin transporter inhibition elucidated by a new flexible docking protocol.
abstract: The two main groups of antidepressant drugs, the tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitors (SSRIs), as well as several other compounds, act by inhibiting the serotonin transporter (SERT). However, the binding mode and molecular mechanism of inhibition in SERT are not fully understood. In this study, five classes of SERT inhibitors were docked into an outward-facing SERT homology model using a new 4D ensemble docking protocol. Unlike other docking protocols, where protein flexibility is not considered or is highly dependent on the ligand structure, flexibility was here obtained by side chain sampling of the amino acids of the binding pocket using biased probability Monte Carlo (BPMC) prior to docking. This resulted in the generation of multiple binding pocket conformations that the ligands were docked into. The docking results showed that the inhibitors were stacked between the aromatic amino acids of the extracellular gate (Y176, F335) presumably preventing its closure. The inhibitors interacted with amino acids in both the putative substrate binding site and more extracellular regions of the protein. A general structure-docking-based pharmacophore model was generated to explain binding of all studied classes of SERT inhibitors. Docking of a test set of actives and decoys furthermore showed that the outward-facing ensemble SERT homology model consistently and selectively scored the majority of active compounds above decoys, which indicates its usefulness in virtual screening.
authors.affiliation: Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, N-9037 Tromsø, Norway.
authors.forename: Mari
authors.initials: M
authors.lastname: Gabrielsen
authors.forename: Rafał
authors.initials: R
authors.lastname: Kurczab
authors.forename: Aina W
authors.initials: AW
authors.lastname: Ravna
authors.forename: Irina
authors.initials: I
authors.lastname: Kufareva
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Zdzisław
authors.initials: Z
authors.lastname: Chilmonczyk
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
mesh_terms: D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D008024:Ligands; D008454:Mazindol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D009010:Monte Carlo Method; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D014326:Tropanes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D008024:Ligands; D008454:Mazindol; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014326:Tropanes
references.citation: J Chem Inf Model. 2010 Jan;50(1):186-93
references.pmid: 20000587
references.citation: Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58
references.pmid: 9537821
references.citation: J Am Chem Soc. 2008 Mar 26;130(12):3853-65
references.pmid: 18314975
references.citation: J Biol Chem. 2010 Mar 12;285(11):8363-74
references.pmid: 19948720
references.citation: J Comput Aided Mol Des. 2008 Sep;22(9):621-7
references.pmid: 18253700
references.citation: J Biol Chem. 2007 Oct 5;282(40):29441-7
references.pmid: 17698848
references.citation: Microbiol Mol Biol Rev. 2000 Jun;64(2):354-411
references.pmid: 10839820
references.citation: Nature. 2007 Aug 23;448(7156):952-6
references.pmid: 17687333
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3785-90
references.pmid: 21282638
references.citation: J Biol Chem. 2006 Nov 24;281(47):36213-20
references.pmid: 17008313
references.citation: J Med Chem. 2010 Jul 22;53(14):5061-84
references.pmid: 20345171
references.citation: Science. 2008 Dec 12;322(5908):1655-61
references.pmid: 19074341
references.citation: Nature. 2005 Sep 8;437(7056):215-23
references.pmid: 16041361
references.citation: Biochim Biophys Acta. 1975 Oct 20;405(2):442-51
references.pmid: 1180967
references.citation: Mol Pharmacol. 2010 Dec;78(6):1026-35
references.pmid: 20829432
references.citation: Nat Struct Mol Biol. 2009 Jun;16(6):652-7
references.pmid: 19430461
references.citation: J Med Chem. 2006 Jan 26;49(2):534-53
references.pmid: 16420040
references.citation: J Mol Model. 2009 Oct;15(10):1155-64
references.pmid: 19238460
references.citation: Curr Opin Struct Biol. 2008 Apr;18(2):178-84
references.pmid: 18302984
references.citation: Synapse. 2010 Nov;64(11):862-9
references.pmid: 20842720
references.citation: Nat Rev Drug Discov. 2005 Sep;4(9):764-74
references.pmid: 16121130
references.citation: J Biol Chem. 2006 Jan 27;281(4):2012-23
references.pmid: 16272152
references.citation: J Med Chem. 2002 Sep 12;45(19):4128-39
references.pmid: 12213056
references.citation: J Neurosci. 2009 Jul 29;29(30):9635-43
references.pmid: 19641126
references.citation: Proteins. 2009 Feb 15;74(3):630-42
references.pmid: 18704946
references.citation: Science. 2007 Sep 7;317(5843):1390-3
references.pmid: 17690258
references.citation: Mol Cell Proteomics. 2005 Jun;4(6):752-61
references.pmid: 15757999
references.citation: Eur J Pharmacol. 2007 Jul 12;567(1-2):1-9
references.pmid: 17499240
references.citation: Structure. 2011 Aug 10;19(8):1108-26
references.pmid: 21827947
references.citation: J Med Chem. 2005 Jun 30;48(13):4432-43
references.pmid: 15974595
references.citation: J Med Chem. 2009 Jan 22;52(2):397-406
references.pmid: 19090659
references.citation: Methods Mol Biol. 2009;575:249-79
references.pmid: 19727619
references.citation: J Mol Recognit. 2009 Jul-Aug;22(4):307-18
references.pmid: 19353579
references.citation: J Chem Inf Model. 2008 Nov;48(11):2214-25
references.pmid: 18954138
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D115-9
references.pmid: 14681372
references.citation: Proteins. 2002 Dec 1;49(4):567-76
references.pmid: 12402365
references.citation: J Biol Chem. 1997 Nov 7;272(45):28321-7
references.pmid: 9353288
references.citation: Mol Pharmacol. 2006 Nov;70(5):1630-42
references.pmid: 16880288
references.citation: J Biol Chem. 1998 Jul 31;273(31):19459-68
references.pmid: 9677366
references.citation: J Med Chem. 2005 Feb 24;48(4):1278-81
references.pmid: 15715498
references.citation: J Neurosci. 1999 Jun 15;19(12):4705-17
references.pmid: 10366604
references.citation: Nature. 1966 Aug 27;211(5052):969-70
references.pmid: 5968307
references.citation: Proteins. 2010 Jan;78(1):197-211
references.pmid: 20063437
references.citation: J Mol Biol. 1994 Jan 21;235(3):983-1002
references.pmid: 8289329
references.citation: Mol Pharmacol. 2001 Mar;59(3):514-23
references.pmid: 11179447
references.citation: J Med Chem. 2003 Jul 3;46(14):3045-59
references.pmid: 12825943
references.citation: J Med Chem. 2001 Feb 15;44(4):502-11
references.pmid: 11170640
references.citation: J Biol Chem. 2009 Apr 10;284(15):10276-84
references.pmid: 19213730
references.citation: J Med Chem. 2006 Jan 12;49(1):92-104
references.pmid: 16392795
references.citation: J Mol Graph Model. 2008 Apr;26(7):1113-24
references.pmid: 18023378
references.citation: J Biol Chem. 2010 Apr 9;285(15):11270-80
references.pmid: 20159976
references.citation: J Chem Inf Comput Sci. 2004 Jan-Feb;44(1):88-96
references.pmid: 14741014
references.citation: J Med Chem. 2005 Mar 10;48(5):1496-505
references.pmid: 15743192
references.citation: Neuropharmacology. 2011 Jan;60(1):108-15
references.pmid: 20637786
references.citation: J Biol Chem. 2004 Jun 4;279(23):24089-99
references.pmid: 15140876
references.citation: J Pharmacol Exp Ther. 2008 Jun;325(3):791-800
references.pmid: 18354055
references.citation: J Biol Chem. 2010 Jan 15;285(3):2051-63
references.pmid: 19892699