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

Affiliation
Department of Pharmacy, School of Pharmaceutical Sciences, University of São Paulo, Av Prof Lineu Prestes 580, Building. 13, São Paulo 05508-000, SP, Brazil;(G.M.F.);
Ferreira, Glaucio Monteiro;
ORCID
0000-0001-6933-7590
Affiliation
Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076 Tübingen, Germany
Kronenberger, Thales;
ORCID
0000-0001-9675-5907
Affiliation
Department of Pharmaceutical Products, Faculty of Pharmacy, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte 31270-901, MG, Brazil
Maltarollo, Vinicius Gonçalves;
ORCID
0000-0003-4196-4204
Affiliation
Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076 Tübingen, Germany
Poso, Antti;
Affiliation
Department of Pharmacy, School of Pharmaceutical Sciences, University of São Paulo, Av Prof Lineu Prestes 580, Building. 13, São Paulo 05508-000, SP, Brazil;(G.M.F.);
de Moura Gatti, Fernando;
Affiliation
Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av Prof Lineu Prestes 748, Building 12, São Paulo 05508-000, SP, Brazil;(V.M.A.);
Almeida, Vitor Medeiros;
Affiliation
Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av Prof Lineu Prestes 748, Building 12, São Paulo 05508-000, SP, Brazil;(V.M.A.);
Marana, Sandro Roberto;
Affiliation
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
Lopes, Carla Duque;
Affiliation
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
Tezuka, Daiane Yukie;
Affiliation
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
de Albuquerque, Sérgio;
Affiliation
Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, Ribeirão Preto 14040-903, SP, Brazil
da Silva Emery, Flavio;
ORCID
0000-0003-3634-2531
Affiliation
Department of Pharmacy, School of Pharmaceutical Sciences, University of São Paulo, Av Prof Lineu Prestes 580, Building. 13, São Paulo 05508-000, SP, Brazil;(G.M.F.);
Trossini, Gustavo Henrique Goulart

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, IC 50 = 40 μM) was chosen as a potential lead compound.

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Editor:
Salmasa, Ramin Ekhteiari; Dardonville, Christophe
Published in:
Pharmaceuticals  
Vol. 16, No. 3 (10.03.2023)
Volume:
16
No.:
3
Date Issued:
10.03.2023
DOI:
10.3390/ph16030428
Language:
English
Type of Resource:
Text
Keywords:
anti-infectives; computer-aided drug discovery; Sirtuin 2; Trypanosoma cruzi
DDC subject of DNB:
610 Medical sciences Medicine

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License Holder: © 2023 by the authors.

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