Drug repurposing for chronic myeloid leukemia: in silico and in vitro investigation of DrugBank database for allosteric Bcr-Abl inhibitors.
J Biomol Struct Dyn
; 35(8): 1833-1848, 2017 Jun.
Article
em En
| MEDLINE
| ID: mdl-27353341
ABSTRACT
Chronic myeloid leukemia (CML) is caused by chromosomal rearrangement resulting in the expression of Bcr-Abl fusion protein with deregulated Abl tyrosine kinase activity. Approved drugs - imatinib, dasatinib, nilotinib, and ponatinib - target the ATP-binding site of Abl kinase. Even though these drugs are initially effective, long-term usefulness is limited by the development of resistance. To overcome this problem, targeting the allosteric site of Abl kinase, which is remote from the ATP-binding site is found to be a useful strategy. In this study, structure-based and ligand-based virtual screening methods were applied to narrow down possible drugs (from DrugBank database) that could target the allosteric site of Abl kinase. Detailed investigations of the selected drugs in the allosteric site of Abl kinase, using molecular dynamics and steered molecular dynamics simulation shows that gefitinib, an EGFR inhibitor approved for the treatment of lung cancer, could bind effectively to the allosteric site of Bcr-Abl. More interestingly, gefitinib was found to enhance the ability of imatinib to bind at the ATP-binding site of Bcr-Abl kinase. Based on the in silico findings, gefitinib was tested in combination with imatinib in K562 CML cell line using MTT cell proliferation assay and found to have a synergistic antiproliferative activity. Further detailed mechanistic study could help to unravel the full potential of imatinib - gefitinib combination for the treatment of CML.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinazolinas
/
Proteínas de Fusão bcr-abl
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Inibidores de Proteínas Quinases
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Reposicionamento de Medicamentos
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Mesilato de Imatinib
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
J Biomol Struct Dyn
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Índia