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

Voice, Angus; Tresadern, Gary; Twidale, Rebecca; Vlijmen, Herman van; Mulholland, Adrian J.

doi:10.1039/d0sc06122k

Cited by 39 publications

(56 citation statements)

References 40 publications

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“…Some classes of inhibitors of SARS-CoV-2 M pro , such as Michael acceptors and ketoamides, , also require a deprotonated Cys145 to covalently bind the active site. Diverse binding mechanisms between inhibitors and enzymes featuring an active-site cysteine have been reported, either involving a direct PT reaction between the inhibitor and the cysteine or requiring a PT reaction from the cysteine to a protein base prior to the binding reaction . In the case of SARS-CoV-2 M pro previous computational works, wherein Michael acceptors , and ketoamides , were investigated, suggested that the physiological PT reaction from Cys145 to His41 occurs prior to covalent binding of the inhibitor.…”

mentioning

confidence: 99%

Tuning Proton Transfer Thermodynamics in SARS-CoV-2 Main Protease: Implications for Catalysis and Inhibitor Design

Zanetti-Polzi

Smith

Chipot

et al. 2021

J. Phys. Chem. Lett.

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The catalytic reaction in SARS-CoV-2 main protease is activated by a proton transfer (PT) from Cys145 to His41. The same PT is likely also required for the covalent binding of some inhibitors. Here we use a multiscale computational approach to investigate the PT thermodynamics in the apo enzyme and in complex with two potent inhibitors, N3 and the α-ketoamide 13b . We show that with the inhibitors the free energy cost to reach the charge-separated state of the active-site dyad is lower, with N3 inducing the most significant reduction. We also show that a few key sites (including specific water molecules) significantly enhance or reduce the thermodynamic feasibility of the PT reaction, with selective desolvation of the active site playing a crucial role. The approach presented is a cost-effective procedure to identify the enzyme regions that control the activation of the catalytic reaction and is thus also useful to guide the design of inhibitors.

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mentioning

confidence: 99%

Tuning Proton Transfer Thermodynamics in SARS-CoV-2 Main Protease: Implications for Catalysis and Inhibitor Design

Zanetti-Polzi

Smith

Chipot

et al. 2021

J. Phys. Chem. Lett.

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“…Given the challenges associated with simultaneous treatment of electronic structure and sampling, multi-scale QM/MM MD is typically employed with both small QM regions (e.g., 30-60 atoms [82][83][84]) and with low-cost, semi-local DFT [85] or semi-empirical QM [86][87][88] (e.g., PM6 or DFTB [89]). To carry out free energy simulations, umbrella sampling has been used by multiple groups [86,87,90] along the methyl transfer coordinate of catechol O-methyltransferase (COMT, Figure 4).…”

Section: Ab Initio and Multi-scale Molecular Dynamicsmentioning

confidence: 99%

Harder, better, faster, stronger: Large-scale QM and QM/MM for predictive modeling in enzymes and proteins

Vennelakanti

Nazemi

Mehmood

et al. 2022

Current Opinion in Structural Biology

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“…Over the last decade, BTK inhibitors have demonstrated e cacy and tolerability in the treatment of B cell malignancies (especially in relapsed or refractory cases [5]), including in chronic lymphocytic leukemia [6,7], diffuse large B cell lymphoma [8], mantle cell lymphoma [9], multiple myeloma [10], and follicular lymphoma [11]. Ibrutinib is the rst covalent irreversible inhibitor of BTK to be used in the treatment of Bcell cancers [12], and it showed anticancer activity in relapsed/refractory multiple myeloma patients when combined with car lzomib/dexamethasone [13][14][15][16]. Three additional agents targeting BTK have been developed: zanubrutinib (BGB-3111) [17], acalabrutinib (ACP-196) [18], and tirabrutinib (ONO/GS-4059) [19].…”

Section: Introductionmentioning

confidence: 99%

Prognostic And Immunological Implications of BTK Expression In Pan-Cancer

Yang¹,

Hao²,

Chen³

et al. 2021

Preprint

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Background: Cancer poses a serious threat to human health. Clarifying the potential significance of Bruton's tyrosine kinase (BTK)in cancer has potential clinical value. This study examined the prognostic and immunological value of BTK gene expression in pan-cancer.Methods: We evaluated the gene expression of BTK in tumor tissues and normal tissues in different cancers. Survival analysis, including Kaplan–Meier analysis and Cox analysis, were performed to explore the prognostic value of BTK for pan-cancer based on survival data from The Cancer Genome Atlas (TCGA) database. Spearman’s method was conducted to analyze the interrelation between BTK gene expression and tumor mutational burden (TMB)and microsatellite instability (MSI). We explored the association of BTK expression with the tumor microenvironment based on Estimation of STromal and Immune cells in MAlignant Tumour tissues using Expression data (ESTIMATE) algorithm. Co-expression analysis of BTK expression and immune-related genes was performed. We used Gene Set Enrichment Analysis (GSEA) to examine the molecular mechanisms and pathways of BTK in pan-cancer.Results: High BTK expression in cervical squamous cell carcinoma and endocervical adenocarcinoma (CSEC), head and neck squamous cell carcinoma (HNSC), lung adenocarcinoma (LUAD) and skin cutaneous melanoma (SKCM) was positively correlated with patient prognosis, while high expression of BTK in lymphoid neoplasm diffuse large B cell lymphoma (DLBC), brain lower grade glioma (LGG) and esophageal carcinoma (ESCA) corresponded with a worse prognosis. Cox analysis showed that BTK was closely associated to the prognosis of HNSC, LGG, SKCM and LUAD. BTK expression was correlated with clinical stage, TMB and MSI of 10 types of tumors. In HNSC, LGG, LUAD and SKCM, the expression of BTK was positive correlated with immune and stromal scores. Conclusion: BTK expression can act as a prognostic factor in various cancers, especially in HNSC, LGG, LUAD and SKCM, and this may be from its close association with TMB, MSI and immune cell infiltration.

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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...

Cited by 39 publications

References 40 publications

Tuning Proton Transfer Thermodynamics in SARS-CoV-2 Main Protease: Implications for Catalysis and Inhibitor Design

Tuning Proton Transfer Thermodynamics in SARS-CoV-2 Main Protease: Implications for Catalysis and Inhibitor Design

Harder, better, faster, stronger: Large-scale QM and QM/MM for predictive modeling in enzymes and proteins

Prognostic And Immunological Implications of BTK Expression In Pan-Cancer

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