Binding of phenothiazines into allosteric hydrophobic pocket of human thioredoxin 1

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS; v. 45, n. 3, p. 279-286, APR 2016.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 12/07456-7 - Estudos por citometria de fluxo de mecanismos de morte e proteção celular promovida por compostos porfirinóides, fenotiazinas e teluranas associadas a nanoestruturas: montagem de uma sala multiusuário de biologia celular
• Beneficiário: Iseli Lourenço Nantes Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/11857-4 - Estudo das interações moleculares entre tioredoxinas/tioredoxinas redutase e inibidores/moduladores alostéricos e caracterização das interações moleculares presentes no sistema Trx
• Beneficiário: Ana Lígia Barbour Scott
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/12247-8 - Novas aplicações de fenotiazinas e paladaciclos: utilização de sistemas nanoestruturados para o estudo dos mecanismos de morte em células tumorais
• Beneficiário: Tiago Rodrigues
• Modalidade de apoio: Auxílio à Pesquisa - Regular