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Identification of potential inhibitors of Mycobacterium tuberculosis shikimate kinase: molecular docking, in silico toxicity and in vitro experiments

Authors :
Talita Freitas de Freitas
Candida Deves Roth
Bruno Lopes Abbadi
Fernanda Souza Macchi Hopf
Marcia Alberton Perelló
Alexia de Matos Czeczot
Eduardo Vieira de Souza
Ana Flávia Borsoi
Pablo Machado
Cristiano Valim Bizarro
Luiz Augusto Basso
Luis Fernando Saraiva Macedo Timmers
Source :
Journal of computer-aided molecular design.
Publication Year :
2022

Abstract

Tuberculosis (TB) is one of the main causes of death from a single pathological agent, Mycobacterium tuberculosis (Mtb). In addition, the emergence of drug-resistant TB strains has exacerbated even further the treatment outcome of TB patients. It is thus needed the search for new therapeutic strategies to improve the current treatment and to circumvent the resistance mechanisms of Mtb. The shikimate kinase (SK) is the fifth enzyme of the shikimate pathway, which is essential for the survival of Mtb. The shikimate pathway is absent in humans, thereby indicating SK as an attractive target for the development of anti-TB drugs. In this work, a combination of in silico and in vitro techniques was used to identify potential inhibitors for SK from Mtb (MtSK). All compounds of our in-house database (Centro de Pesquisas em Biologia Molecular e Funcional, CPBMF) were submitted to in silico toxicity analysis to evaluate the risk of hepatotoxicity. Docking experiments were performed to identify the potential inhibitors of MtSK according to the predicted binding energy. In vitro inhibitory activity of MtSK-catalyzed chemical reaction at a single compound concentration was assessed. Minimum inhibitory concentration values for in vitro growth of pan-sensitive Mtb H37Rv strain were also determined. The mixed approach implemented in this work was able to identify five compounds that inhibit both MtSK and the in vitro growth of Mtb.

Details

ISSN :
15734951
Database :
OpenAIRE
Journal :
Journal of computer-aided molecular design
Accession number :
edsair.doi.dedup.....1930acb0b3493be95dd9a1710dd85e10