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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Binding of phenothiazines into allosteric hydrophobic pocket of human thioredoxin 1

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Author(s):
Philot, Eric Allison [1] ; Lopes, David da Mata [1] ; de Souza, Aryane Tofanello [1] ; Kimus Braz, Antonio Sergio [1] ; Nantes, Iseli Lourenco [1] ; Rodrigues, Tiago [1] ; Perahia, David [2] ; Miteva, Maria A. [3, 4] ; Barbour Scott, Luis Paulo [5]
Total Authors: 9
Affiliation:
[1] Univ Fed ABC, Ctr Ciencias Nat & Humanas, Santo Andre, SP - Brazil
[2] ENS Cachan, CNRS, Lab Biol & Pharmacol Appl, Cachan - France
[3] Univ Paris Diderot, Sorbonne Paris Cite, Mol Therapeut In Silico, INSERM, UMR S 973, Paris - France
[4] INSERM, U973, Paris - France
[5] Univ Fed ABC, Ctr Matemat Comp & Cognicao, Santo Andre, SP - Brazil
Total Affiliations: 5
Document type: Journal article
Source: EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS; v. 45, n. 3, p. 279-286, APR 2016.
Web of Science Citations: 0
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. (AU)

FAPESP's process: 12/07456-7 - Flow cytometry studies of cell death and protection promoted by porphyrinoid compounds, phenothiazines and Teluranes associated to nanostructures in a cell biology multiuser lab
Grantee:Iseli Lourenço Nantes Cardoso
Support Opportunities: Regular Research Grants
FAPESP's process: 11/11857-4 - Study of moleuclar interactions among thioredoxin/thioredoxin reductase and inhibitors and alosteric modulators the characterization of moecular interactions presents in the system Trx
Grantee:Ana Ligia Scott
Support Opportunities: Regular Research Grants
FAPESP's process: 12/12247-8 - New applications of phenothiazines and Palladacycles: nanostructured systems to the mechanistic study of death in tumor cells
Grantee:Tiago Rodrigues
Support Opportunities: Regular Research Grants