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

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

doi:10.3390/ph16030428

Pharmaceuticals (Mar 2023)

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

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

Affiliations

Glaucio Monteiro Ferreira: Department of Pharmacy, School of Pharmaceutical Sciences, University of São Paulo, Av Prof Lineu Prestes 580, Building. 13, São Paulo 05508-000, SP, Brazil
Thales Kronenberger: Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076 Tübingen, Germany
Vinicius Gonçalves Maltarollo: Department of Pharmaceutical Products, Faculty of Pharmacy, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte 31270-901, MG, Brazil
Antti Poso: Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076 Tübingen, Germany
Fernando de Moura Gatti: Department of Pharmacy, School of Pharmaceutical Sciences, University of São Paulo, Av Prof Lineu Prestes 580, Building. 13, São Paulo 05508-000, SP, Brazil
Vitor Medeiros Almeida: Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av Prof Lineu Prestes 748, Building 12, São Paulo 05508-000, SP, Brazil
Sandro Roberto Marana: Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av Prof Lineu Prestes 748, Building 12, São Paulo 05508-000, SP, Brazil
Carla Duque Lopes: Department of Clinical Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, Ribeirão Preto 14040-903, SP, Brazil
Daiane Yukie Tezuka: Department of Clinical Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, Ribeirão Preto 14040-903, SP, Brazil
Sérgio de Albuquerque: Department of Clinical Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, Ribeirão Preto 14040-903, SP, Brazil
Flavio da Silva Emery: Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, Ribeirão Preto 14040-903, SP, Brazil
Gustavo Henrique Goulart Trossini: Department of Pharmacy, School of Pharmaceutical Sciences, University of São Paulo, Av Prof Lineu Prestes 580, Building. 13, São Paulo 05508-000, SP, Brazil

DOI: https://doi.org/10.3390/ph16030428
Journal volume & issue: Vol. 16, no. 3
p. 428

Abstract

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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 μM) was chosen as a potential lead compound.

Published in Pharmaceuticals

ISSN: 1424-8247 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Pharmacy and materia medica
Website: http://www.mdpi.com/journal/pharmaceuticals/

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