Trypanosoma cruzi Sirtuin 2 as a Relevant Druggable Target: New Inhibitors Developed by Computer-Aided Drug Design-Reference-Cited by-同舟云学术

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

Published:2023-03-10 Issue:3 Volume:16 Page:428
ISSN:1424-8247
Container-title:Pharmaceuticals
language:en
Short-container-title:Pharmaceuticals

Author:

Ferreira Glaucio Monteiro¹²,Kronenberger Thales³⁴^ORCID,Maltarollo Vinicius Gonçalves⁵^ORCID,Poso Antti³⁴^ORCID,de Moura Gatti Fernando¹,Almeida Vitor Medeiros⁶,Marana Sandro Roberto⁶,Lopes Carla Duque⁷,Tezuka Daiane Yukie⁷,de Albuquerque Sérgio⁷,da Silva Emery Flavio⁸,Trossini Gustavo Henrique Goulart¹^ORCID

Affiliation:

1. Department of Pharmacy, School of Pharmaceutical Sciences, University of São Paulo, Av Prof Lineu Prestes 580, Building. 13, São Paulo 05508-000, SP, Brazil

2. Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, Av Prof Lineu Prestes 580, Building. 17, São Paulo 05508-000, SP, Brazil

3. Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076 Tübingen, Germany

4. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland

5. Department of Pharmaceutical Products, Faculty of Pharmacy, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte 31270-901, MG, Brazil

6. Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av Prof Lineu Prestes 748, Building 12, São Paulo 05508-000, SP, Brazil

7. 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

8. Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, Ribeirão Preto 14040-903, SP, Brazil

Abstract

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.

Funder

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

Publisher

MDPI AG

Subject

Drug Discovery,Pharmaceutical Science,Molecular Medicine

Link

https://www.mdpi.com/1424-8247/16/3/428/pdf

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