Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations

Angus T Voice; Gary Tresadern; Rebecca M Twidale; Herman van Vlijmen; Adrian J Mulholland

doi:10.1039/D0SC06122K

Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations

Angus T Voice, Gary Tresadern, Rebecca M Twidale, Herman van Vlijmen, Adrian J Mulholland

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Abstract

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.

Original language	English
Pages (from-to)	5511-5516
Number of pages	6
Journal	Chemical Science
Volume	12
Issue number	15
DOIs	https://doi.org/10.1039/D0SC06122K https://doi.org/10.1039/d0sc06122k
Publication status	Published - 28 Jan 2021

Bibliographical note

Funding Information:
This work was supported by Janssen through a PhD studentship to A. T. V. A. J. M. thanks EPSRC for funding to CCP-BioSim (http://www.ccpbiosim.ac.uk) [grant number EP/M022609/1]. This work was carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol (http://www.bristol.ac.uk/acrc/). We thank Alan Gross-eld for his code for WHAM analysis.

Funding Information:
This work was supported by Janssen through a PhD studentship to A. T. V. A. J. M. thanks EPSRC for funding to CCP-BioSim (http://www.ccpbiosim.ac.uk) [grant number EP/M022609/1]. This work was carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol (http://www.bristol.ac.uk/acrc/). We thank Alan Grossfield for his code for WHAM analysis.

Publisher Copyright:
© The Royal Society of Chemistry 2021.

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title = "Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations",

abstract = "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.",

author = "Voice, {Angus T} and Gary Tresadern and Twidale, {Rebecca M} and {van Vlijmen}, Herman and Mulholland, {Adrian J}",

note = "Funding Information: This work was supported by Janssen through a PhD studentship to A. T. V. A. J. M. thanks EPSRC for funding to CCP-BioSim (http://www.ccpbiosim.ac.uk) [grant number EP/M022609/1]. This work was carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol (http://www.bristol.ac.uk/acrc/). We thank Alan Gross-eld for his code for WHAM analysis. Funding Information: This work was supported by Janssen through a PhD studentship to A. T. V. A. J. M. thanks EPSRC for funding to CCP-BioSim (http://www.ccpbiosim.ac.uk) [grant number EP/M022609/1]. This work was carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol (http://www.bristol.ac.uk/acrc/). We thank Alan Grossfield for his code for WHAM analysis. Publisher Copyright: {\textcopyright} The Royal Society of Chemistry 2021.",

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AU - Voice, Angus T

AU - Tresadern, Gary

AU - Twidale, Rebecca M

AU - van Vlijmen, Herman

AU - Mulholland, Adrian J

N1 - Funding Information: This work was supported by Janssen through a PhD studentship to A. T. V. A. J. M. thanks EPSRC for funding to CCP-BioSim (http://www.ccpbiosim.ac.uk) [grant number EP/M022609/1]. This work was carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol (http://www.bristol.ac.uk/acrc/). We thank Alan Gross-eld for his code for WHAM analysis. Funding Information: This work was supported by Janssen through a PhD studentship to A. T. V. A. J. M. thanks EPSRC for funding to CCP-BioSim (http://www.ccpbiosim.ac.uk) [grant number EP/M022609/1]. This work was carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol (http://www.bristol.ac.uk/acrc/). We thank Alan Grossfield for his code for WHAM analysis. Publisher Copyright: © The Royal Society of Chemistry 2021.

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N2 - 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.

AB - 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.

U2 - 10.1039/D0SC06122K

DO - 10.1039/D0SC06122K

M3 - Article (Academic Journal)

C2 - 33995994

SN - 2041-6520

VL - 12

SP - 5511

EP - 5516

JO - Chemical Science

JF - Chemical Science

IS - 15

ER -

Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations

Abstract

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