title: Drug repurposing for chronic myeloid leukemia: in silico and in vitro investigation of DrugBank database for allosteric Bcr-Abl inhibitors.
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.
authors.affiliation: a School of Life Sciences, Centre for Bioinformatics , Pondicherry University , Kalapet , Puducherry 605014 , India.
authors.forename: Vivek Kumar
authors.initials: VK
authors.lastname: Singh
authors.affiliation: b Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , 35 Keyan Road, Zhunan, Miaoli County 350 , Taiwan, ROC.
authors.forename: Hsin-Huei
authors.initials: HH
authors.lastname: Chang
authors.affiliation: b Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , 35 Keyan Road, Zhunan, Miaoli County 350 , Taiwan, ROC.|c Institute of Clinical Pharmacy and Pharmaceutical Sciences , National Cheng Kung University Medical College , Tainan , Taiwan.|d Graduate Program for Aging , China Medical University , Taichung , Taiwan, ROC.
authors.forename: Ching-Chuan
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: b Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , 35 Keyan Road, Zhunan, Miaoli County 350 , Taiwan, ROC.
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Shiao
authors.affiliation: b Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , 35 Keyan Road, Zhunan, Miaoli County 350 , Taiwan, ROC.|e Department of Chemistry , National Tsing Hua University , Hsinchu , Taiwan, ROC.
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
authors.affiliation: a School of Life Sciences, Centre for Bioinformatics , Pondicherry University , Kalapet , Puducherry 605014 , India.
authors.forename: Mohane Selvaraj
authors.initials: MS
authors.lastname: Coumar
mesh_terms: D000495:Allosteric Site; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D020134:Catalytic Domain; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib / Q000494:pharmacology; D062126:Databases, Chemical; D004338:Drug Combinations; D058492:Drug Repositioning; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D020014:K562 Cells; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000068877:Imatinib Mesylate; C512478:EGFR protein, human; D066246:ErbB Receptors; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib; D000077156:Gefitinib
keywords: Bcr-Abl inhibitor; allosteric inhibitor; chronic myeloid leukemia; drug repurposing; molecular dynamics simulation; steered molecular dynamics simulation; virtual screening