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Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations
Ibrutinib is the first covalent inhibitor of Bruton's tyrosine kinase (BTK) to be used in the treatment of B-cell cancers. Understanding the mechanism of covalent inhibition will aid in the design of safer and more selective covalent inhibitors that target BTK. The mechanism of covalent inhibit...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097726/ https://www.ncbi.nlm.nih.gov/pubmed/33995994 http://dx.doi.org/10.1039/d0sc06122k |
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author | Voice, Angus T. Tresadern, Gary Twidale, Rebecca M. van Vlijmen, Herman Mulholland, Adrian J. |
author_facet | Voice, Angus T. Tresadern, Gary Twidale, Rebecca M. van Vlijmen, Herman Mulholland, Adrian J. |
author_sort | Voice, Angus T. |
collection | PubMed |
description | Ibrutinib is the first covalent inhibitor of Bruton's tyrosine kinase (BTK) to be used in the treatment of B-cell cancers. Understanding the mechanism of covalent inhibition will aid in the design of safer and more selective covalent inhibitors that target BTK. The mechanism of covalent inhibition in BTK has been uncertain because there is no appropriate residue nearby that can act as a base to deprotonate the cysteine thiol prior to covalent bond formation. We investigate several mechanisms of covalent modification of C481 in BTK by ibrutinib using combined quantum mechanics/molecular mechanics (QM/MM) molecular dynamics reaction simulations. The lowest energy pathway involves direct proton transfer from C481 to the acrylamide warhead in ibrutinib, followed by covalent bond formation to form an enol intermediate. There is a subsequent rate-limiting keto–enol tautomerisation step (ΔG(‡) = 10.5 kcal mol(−1)) to reach the inactivated BTK/ibrutinib complex. Our results represent the first mechanistic study of BTK inactivation by ibrutinib to consider multiple mechanistic pathways. These findings should aid in the design of covalent drugs that target BTK and other similar targets. |
format | Online Article Text |
id | pubmed-8097726 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-80977262021-05-13 Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations Voice, Angus T. Tresadern, Gary Twidale, Rebecca M. van Vlijmen, Herman Mulholland, Adrian J. Chem Sci Chemistry Ibrutinib is the first covalent inhibitor of Bruton's tyrosine kinase (BTK) to be used in the treatment of B-cell cancers. Understanding the mechanism of covalent inhibition will aid in the design of safer and more selective covalent inhibitors that target BTK. The mechanism of covalent inhibition in BTK has been uncertain because there is no appropriate residue nearby that can act as a base to deprotonate the cysteine thiol prior to covalent bond formation. We investigate several mechanisms of covalent modification of C481 in BTK by ibrutinib using combined quantum mechanics/molecular mechanics (QM/MM) molecular dynamics reaction simulations. The lowest energy pathway involves direct proton transfer from C481 to the acrylamide warhead in ibrutinib, followed by covalent bond formation to form an enol intermediate. There is a subsequent rate-limiting keto–enol tautomerisation step (ΔG(‡) = 10.5 kcal mol(−1)) to reach the inactivated BTK/ibrutinib complex. Our results represent the first mechanistic study of BTK inactivation by ibrutinib to consider multiple mechanistic pathways. These findings should aid in the design of covalent drugs that target BTK and other similar targets. The Royal Society of Chemistry 2021-01-28 /pmc/articles/PMC8097726/ /pubmed/33995994 http://dx.doi.org/10.1039/d0sc06122k Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/ |
spellingShingle | Chemistry Voice, Angus T. Tresadern, Gary Twidale, Rebecca M. van Vlijmen, Herman Mulholland, Adrian J. Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations |
title | Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations |
title_full | Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations |
title_fullStr | Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations |
title_full_unstemmed | Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations |
title_short | Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations |
title_sort | mechanism of covalent binding of ibrutinib to bruton's tyrosine kinase revealed by qm/mm calculations |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097726/ https://www.ncbi.nlm.nih.gov/pubmed/33995994 http://dx.doi.org/10.1039/d0sc06122k |
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