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Drug repurposing for chronic myeloid leukemia: in silico and in vitro investigation of DrugBank database for allosteric Bcr-Abl inhibitors.
- Source :
-
Journal of biomolecular structure & dynamics [J Biomol Struct Dyn] 2017 Jun; Vol. 35 (8), pp. 1833-1848. Date of Electronic Publication: 2016 Jun 29. - Publication Year :
- 2017
-
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.
- Subjects :
- Allosteric Site
Binding Sites
Catalytic Domain
Cell Proliferation drug effects
Dasatinib pharmacology
Databases, Chemical
Drug Combinations
Drug Resistance, Neoplasm
Drug Synergism
ErbB Receptors antagonists & inhibitors
ErbB Receptors chemistry
Fusion Proteins, bcr-abl chemistry
Fusion Proteins, bcr-abl metabolism
Gefitinib
Humans
K562 Cells
Molecular Dynamics Simulation
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Quinazolines chemistry
Thermodynamics
Antineoplastic Agents pharmacology
Drug Repositioning
Fusion Proteins, bcr-abl antagonists & inhibitors
Imatinib Mesylate pharmacology
Protein Kinase Inhibitors pharmacology
Quinazolines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-0254
- Volume :
- 35
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of biomolecular structure & dynamics
- Publication Type :
- Academic Journal
- Accession number :
- 27353341
- Full Text :
- https://doi.org/10.1080/07391102.2016.1196462