Trypanosoma cruzi Sirtuin 2 as a Relevant Druggable Target: New Inhibitors Developed by Computer-Aided Drug Design

Autor(es):Mostrar menos -

Ferreira, Glaucio Monteiro ; Kronenberger, Thales ; Maltarollo, Vinicius Goncalves ; Poso, Antti ; Gatti, Fernando de Moura ; Almeida, Vitor Medeiros ; Marana, Sandro Roberto ; Lopes, Carla Duque ; Tezuka, Daiane Yukie ; de Albuquerque, Sergio ; Emery, Flavio da Silva ; Trossini, Gustavo Henrique Goulart

• Tipo de documento: Artigo Científico
• Fonte: PHARMACEUTICALS; v. 16, n. 3, p. 14-pg., 2023-03-01.

Resumo

Trypanosoma cruzi, the etiological agent of Chagas disease, relies on finely coordinated epigenetic regulation during the transition between hosts. Herein we targeted the silent information regulator 2 (Sir2) enzyme, a NAD(+)-dependent class III histone deacetylase, to interfere with the parasites' cell cycle. A combination of molecular modelling with on-target experimental validation was used to discover new inhibitors from commercially available compound libraries. We selected six inhibitors from the virtual screening, which were validated on the recombinant Sir2 enzyme. The most potent inhibitor (CDMS-01, IC50 = 40 mu M) was chosen as a potential lead compound. (AU)

• Processo FAPESP: 16/22365-9 - Redes estruturais e dinâmica em enzimas
• Beneficiário: Sandro Roberto Marana
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 19/06172-4 - Bolsa de PD em busca de novos fármacos contra Hipercolesterolemia, baseados em marcadores genéticos e epigenéticos específicos da população brasileira
• Beneficiário: Glaucio Monteiro Ferreira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 17/25543-8 - Estratégias de Química Medicinal (LBDD e SBDD) na busca de inibidores de Sirtuína 2 de tripanossomatídeos
• Beneficiário: Gustavo Henrique Goulart Trossini
• Modalidade de apoio: Auxílio à Pesquisa - Regular