title: Binding of phenothiazines into allosteric hydrophobic pocket of human thioredoxin 1.
abstract: Thioredoxins are multifunctional oxidoreductase proteins implicated in the antioxidant cellular apparatus and oxidative stress. They are involved in several pathologies and are promising anticancer targets. Identification of noncatalytic binding sites is of great interest for designing new allosteric inhibitors of thioredoxin. In a recent work, we predicted normal mode motions of human thioredoxin 1 and identified two major putative hydrophobic binding sites. In this work we investigated noncovalent interactions of human thioredoxin 1 with three phenotiazinic drugs acting as prooxidant compounds by using molecular docking and circular dichroism spectrometry to probe ligand binding into the previously predicted allosteric hydrophobic pockets. Our in silico and CD spectrometry experiments suggested one preferred allosteric binding site involving helix 3 and adopting the best druggable conformation identified by NMA. The CD spectra showed binding of thioridazine into thioredoxin 1 and suggested partial helix unfolding, which most probably concerns helix 3. Taken together, these data support the strategy to design thioredoxin inhibitors targeting a druggable allosteric binding site.
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brazil.
authors.forename: Eric Allison
authors.initials: EA
authors.lastname: Philot
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brazil.
authors.forename: David
authors.initials: D
authors.lastname: da Mata Lopes
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brazil.
authors.forename: Aryane Tofanello
authors.initials: AT
authors.lastname: de Souza
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brazil.
authors.forename: Antônio Sérgio Kimus
authors.initials: AS
authors.lastname: Braz
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brazil.
authors.forename: Iseli Lourenço
authors.initials: IL
authors.lastname: Nantes
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brazil.
authors.forename: Tiago
authors.initials: T
authors.lastname: Rodrigues
authors.affiliation: Laboaratorie de Biologie et de Pharmacologie Appliquéee, ENS de Cachan, Centre National de la Research Scientific, Cachan, France.
authors.forename: David
authors.initials: D
authors.lastname: Perahia
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques In Silico, INSERM UMR-S 973, Paris, France. maria.miteva@univ-paris-diderot.fr.|INSERM, U973, Paris, France. maria.miteva@univ-paris-diderot.fr.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Miteva
authors.affiliation: Centro de Matemática Computação e Cognição, Universidade Federal do ABC, Santo André, SP, Brazil. luisp37@gmail.com.
authors.forename: Luis Paulo Barbour
authors.initials: LP
authors.lastname: Scott
mesh_terms: D000495:Allosteric Site; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D013879:Thioredoxins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010640:Phenothiazines; D013879:Thioredoxins; C031637:phenothiazine
keywords: Allosteric inhibitors; Docking; Normal modes; Phenothiazines; Thioredoxin
references.citation: Oncol Res. 1997;9(6-7):351-6
references.pmid: 9406241
references.citation: Sci Rep. 2011;1:179
references.pmid: 22355694
references.citation: Arch Toxicol. 1988;62(2-3):185-91
references.pmid: 2904251
references.citation: Compr Psychiatry. 1999 Nov-Dec;40(6):407-14
references.pmid: 10579370
references.citation: J Comput Chem. 2009 Jul 30;30(10):1545-614
references.pmid: 19444816
references.citation: J Biol Chem. 1994 Apr 22;269(16):11714-20
references.pmid: 8163468
references.citation: Bioinformatics. 2012 Jan 15;28(2):286-7
references.pmid: 22113084
references.citation: In Vivo. 2004 Nov-Dec;18(6):725-31
references.pmid: 15646813
references.citation: Biochemistry. 2014 May 13;53(18):2890-902
references.pmid: 24738963
references.citation: Biochem Pharmacol. 2010 Oct 15;80(8):1284-95
references.pmid: 20619250
references.citation: FEBS Lett. 2006 Oct 2;580(22):5130-6
references.pmid: 16962102
references.citation: Drug Discov Today. 2011 Feb;16(3-4):119-31
references.pmid: 21237283
references.citation: Structure. 1995 Mar 15;3(3):239-43
references.pmid: 7788289
references.citation: Antioxid Redox Signal. 2013 Oct 10;19(11):1266-303
references.pmid: 23244617
references.citation: J Med Pharm Chem. 1960 Dec;2:659-68
references.pmid: 13696194
references.citation: Mol Nutr Food Res. 2009 Jan;53(1):87-103
references.pmid: 18979503
references.citation: Annu Rev Genet. 2009;43:335-67
references.pmid: 19691428
references.citation: Free Radic Res. 2010 Sep;44(9):1054-63
references.pmid: 20815768
references.citation: Mol Pharmacol. 2005 Jan;67(1):97-104
references.pmid: 15492117
references.citation: Antioxid Redox Signal. 2013 Apr 1;18(10):1165-207
references.pmid: 22607099
references.citation: Eur J Biochem. 2000 Oct;267(20):6102-9
references.pmid: 11012661
references.citation: J Struct Biol. 2013 Nov;184(2):293-300
references.pmid: 24036282
references.citation: Oxid Med Cell Longev. 2015;2015:394367
references.pmid: 26075034
references.citation: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W622-7
references.pmid: 20444874
references.citation: J Comput Chem. 2010 Jan 30;31(2):455-61
references.pmid: 19499576
references.citation: Int J Mol Sci. 2012 Nov 06;13(11):14326-43
references.pmid: 23203067
references.citation: Toxicology. 2015 Apr 1;330:44-54
references.pmid: 25686698
references.citation: Biochem Biophys Res Commun. 2010 May 21;396(1):120-4
references.pmid: 20494123
references.citation: Br J Pharmacol. 2002 May;136(1):136-42
references.pmid: 11976278
references.citation: Biochem Biophys Res Commun. 2006 Dec 8;351(1):273-80
references.pmid: 17056009
references.citation: J Comput Aided Mol Des. 2010 May;24(5):417-22
references.pmid: 20401516
references.citation: Protein Sci. 2010 Sep;19(9):1801-6
references.pmid: 20662007
references.citation: Biochemistry. 1991 Mar 12;30(10):2685-98
references.pmid: 2001356
references.citation: Semin Cancer Biol. 2006 Dec;16(6):420-6
references.pmid: 17092741
references.citation: Structure. 1994 Jun 15;2(6):503-22
references.pmid: 7922028
references.citation: J Comput Aided Mol Des. 1999 Nov;13(6):547-62
references.pmid: 10584214
references.citation: J Med Chem. 2013 Feb 14;56(3):1301-10
references.pmid: 23327656
references.citation: Neuropharmacology. 2012 Aug;63(2):280-91
references.pmid: 22507664
references.citation: Clin Cancer Res. 2007 Apr 1;13(7):2109-14
references.pmid: 17404093
references.citation: Cancer Chemother Pharmacol. 2011 Mar;67(3):503-9
references.pmid: 20461382