Binding of phenothiazines into allosteric hydrophobic pocket of human thioredoxin 1
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- 作者：Eric Allison Philot ; David da Mata Lopes…
- 关键词：Thioredoxin ; Allosteric inhibitors ; Docking ; Normal modes ; Phenothiazines
- 刊名：European Biophysics Journal
- 出版年：2016
- 出版时间：April 2016
- 年：2016
- 卷：45
- 期：3
- 页码：279-286
- 全文大小：1,549 KB
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David da Mata Lopes (1)
Aryane Tofanello de Souza (1)
Antônio Sérgio Kimus Braz (1)
Iseli Lourenço Nantes (1)
Tiago Rodrigues (1)
David Perahia (2)
Maria A. Miteva (3) (4)
Luis Paulo Barbour Scott (5)
1. Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brazil
2. Laboaratorie de Biologie et de Pharmacologie Appliquéee, ENS de Cachan, Centre National de la Research Scientific, Cachan, France
3. Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques In Silico, INSERM UMR-S 973, Paris, France
4. INSERM, U973, Paris, France
5. Centro de Matemática Computação e Cognição, Universidade Federal do ABC, Santo André, SP, Brazil - 刊物类别：Physics and Astronomy
- 刊物主题：Physics
Biophysics and Biomedical Physics
Cell Biology
Biochemistry
Plant Physiology
Animal Physiology
Neurobiology - 出版者：Springer Berlin / Heidelberg
- ISSN：1432-1017
文摘
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.