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Ponatinib Is a Pan-BCR-ABL Kinase Inhibitor: MD Simulations and SIE Study
BCR-ABL kinase domain inhibition can be used to treat chronic myeloid leukemia. The inhibitors such as imatinib, dasatinib and nilotinib are effective drugs but are resistant to some BCR-ABL mutations. The pan-BCR-ABL kinase inhibitor ponatinib exhibits potent activity against native, T315I, and all...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827254/ https://www.ncbi.nlm.nih.gov/pubmed/24236021 http://dx.doi.org/10.1371/journal.pone.0078556 |
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author | Tanneeru, Karunakar Guruprasad, Lalitha |
author_facet | Tanneeru, Karunakar Guruprasad, Lalitha |
author_sort | Tanneeru, Karunakar |
collection | PubMed |
description | BCR-ABL kinase domain inhibition can be used to treat chronic myeloid leukemia. The inhibitors such as imatinib, dasatinib and nilotinib are effective drugs but are resistant to some BCR-ABL mutations. The pan-BCR-ABL kinase inhibitor ponatinib exhibits potent activity against native, T315I, and all other clinically relevant mutants, and showed better inhibition than the previously known inhibitors. We have studied the molecular dynamics simulations and calculated solvated interaction energies of native and fourteen mutant BCR-ABL kinases (M244V, G250E, Q252H, Y253F, Y253H, E255K, E255V, T315A, T315I, F317L, F317V, M351T, F359V and H396P) complexed with ponatinib. These studies revealed that the interactions between ponatinib and individual residues in BCR-ABL kinase are also affected due to the remote residue mutations. We report that some residues, Met244, Lys245, Gln252, Gly254, Leu370 and Leu298 do not undergo any conformational changes, while the fluctuations in residues from P-loop, β3-, β5- strands and αC- helix are mainly responsible for ponatinib binding to native and all mutant BCR-ABL kinases. Our work provides the molecular mechanisms of native and mutant BCR-ABL kinases inhibition by ponatinib at atomic level that has not been studied before. |
format | Online Article Text |
id | pubmed-3827254 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-38272542013-11-14 Ponatinib Is a Pan-BCR-ABL Kinase Inhibitor: MD Simulations and SIE Study Tanneeru, Karunakar Guruprasad, Lalitha PLoS One Research Article BCR-ABL kinase domain inhibition can be used to treat chronic myeloid leukemia. The inhibitors such as imatinib, dasatinib and nilotinib are effective drugs but are resistant to some BCR-ABL mutations. The pan-BCR-ABL kinase inhibitor ponatinib exhibits potent activity against native, T315I, and all other clinically relevant mutants, and showed better inhibition than the previously known inhibitors. We have studied the molecular dynamics simulations and calculated solvated interaction energies of native and fourteen mutant BCR-ABL kinases (M244V, G250E, Q252H, Y253F, Y253H, E255K, E255V, T315A, T315I, F317L, F317V, M351T, F359V and H396P) complexed with ponatinib. These studies revealed that the interactions between ponatinib and individual residues in BCR-ABL kinase are also affected due to the remote residue mutations. We report that some residues, Met244, Lys245, Gln252, Gly254, Leu370 and Leu298 do not undergo any conformational changes, while the fluctuations in residues from P-loop, β3-, β5- strands and αC- helix are mainly responsible for ponatinib binding to native and all mutant BCR-ABL kinases. Our work provides the molecular mechanisms of native and mutant BCR-ABL kinases inhibition by ponatinib at atomic level that has not been studied before. Public Library of Science 2013-11-13 /pmc/articles/PMC3827254/ /pubmed/24236021 http://dx.doi.org/10.1371/journal.pone.0078556 Text en © 2013 Tanneeru, Guruprasad http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Tanneeru, Karunakar Guruprasad, Lalitha Ponatinib Is a Pan-BCR-ABL Kinase Inhibitor: MD Simulations and SIE Study |
title | Ponatinib Is a Pan-BCR-ABL Kinase Inhibitor: MD Simulations and SIE Study |
title_full | Ponatinib Is a Pan-BCR-ABL Kinase Inhibitor: MD Simulations and SIE Study |
title_fullStr | Ponatinib Is a Pan-BCR-ABL Kinase Inhibitor: MD Simulations and SIE Study |
title_full_unstemmed | Ponatinib Is a Pan-BCR-ABL Kinase Inhibitor: MD Simulations and SIE Study |
title_short | Ponatinib Is a Pan-BCR-ABL Kinase Inhibitor: MD Simulations and SIE Study |
title_sort | ponatinib is a pan-bcr-abl kinase inhibitor: md simulations and sie study |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827254/ https://www.ncbi.nlm.nih.gov/pubmed/24236021 http://dx.doi.org/10.1371/journal.pone.0078556 |
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