In Vitro and In Silico Characterization of an Antimalarial Compound with Antitumor Activity Targeting Human DNA Topoisomerase IB.
Int J Mol Sci
; 22(14)2021 Jul 12.
Article
em En
| MEDLINE
| ID: mdl-34299074
ABSTRACT
Human DNA topoisomerase IB controls the topological state of supercoiled DNA through a complex catalytic cycle that consists of cleavage and religation reactions, allowing the progression of fundamental DNA metabolism. The catalytic steps of human DNA topoisomerase IB were analyzed in the presence of a drug, obtained by the open-access drug bank Medicines for Malaria Venture. The experiments indicate that the compound strongly and irreversibly inhibits the cleavage step of the enzyme reaction and reduces the cell viability of three different cancer cell lines. Molecular docking and molecular dynamics simulations suggest that the drug binds to the human DNA topoisomerase IB-DNA complex sitting inside the catalytic site of the enzyme, providing a molecular explanation for the cleavage-inhibition effect. For all these reasons, the aforementioned drug could be a possible lead compound for the development of an efficient anti-tumor molecule targeting human DNA topoisomerase IB.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Simulação por Computador
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DNA
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DNA Topoisomerases Tipo I
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Inibidores da Topoisomerase I
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Antimaláricos
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article