The inhibitory effect of helenalin on telomerase activity is attributed to the alkylation of the CYS445 residue: Evidence from QM/MM simulations

Zhang, Zhiqiang; Xu, Liancai; Cheung, Hon-Yeung

doi:10.1016/j.jmgm.2014.04.012

Cited by 8 publications

(5 citation statements)

References 44 publications

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“…Therefore, we utilized water molecules as a vehicle instead of other residues to transfer protons in these simplified models. The similar reversible Michael addition mechanism, in which water molecules were considered as the proton shuttle in the reaction, was published in previous studies . Moreover, the energy barrier obtained in our studies was in reasonable agreement with the experimental one.…”

Section: Resultssupporting

confidence: 91%

“…The similar reversible Michael addition mechanism, in which water molecules were considered as the proton shuttle in the reaction, was published in previous studies. 63 Moreover, the energy barrier obtained in our studies was in reasonable agreement with the experimental one. Take L11−EGFR as an example: first, water molecules form hydrogen bonds with the nitrile group of compound L11 (Figure 5).…”

Section: Computational Studies Of the Elimination Of Thiol Adducts (C...supporting

confidence: 89%

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Discovery and Computational Studies of Potent Covalent Kinase Inhibitors with α-Substituent Electrophiles Targeting Cysteine

Yang

et al. 2023

J. Chem. Inf. Model.

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Both reversible noncovalent inhibitors and irreversible covalent inhibitors targeting tyrosine kinases have their disadvantages. The reversible covalent inhibitors with electrophilic group cyanoacrylamide as warheads reacting with cysteine residues could solve the dilemmas. However, there are still several unresolved issues regarding the electrophilic groups. In this manuscript, a series of EGFR inhibitors with double electron-withdrawing substituents introduced into the C α position on the olefin bond were designed and synthesized. The binding structures and characteristics of inhibitors with the kinase in both the first noncovalent binding phase and the second covalent binding step were explored and combined with molecular docking and molecular dynamics simulations. Then, the reverse β-elimination reactions of the thiol-Michael adducts were investigated by applying density functional theory calculations. In addition, the effects of different electrophilic substituents of C α on the binding between the inhibitors and kinase were elucidated. The results suggested that the electrophilicity and size of the electronwithdrawing groups play an important role in the specific interactions during the reaction. The compounds with the electronwithdrawing groups that had medium electrostatic and steric complementarity to the kinase active site could cooperatively stabilize the complexes and showed relatively good potent activities in the kinase assay experiment. The mechanical and structural information in this study could enhance our understanding of the functioning of the electron-withdrawing groups in the covalent inhibitors. The results might help to design efficient cysteine targeting inhibitors in the future.

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Section: Resultssupporting

confidence: 91%

Section: Computational Studies Of the Elimination Of Thiol Adducts (C...supporting

confidence: 89%

Discovery and Computational Studies of Potent Covalent Kinase Inhibitors with α-Substituent Electrophiles Targeting Cysteine

Yang

et al. 2023

J. Chem. Inf. Model.

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“…9 Acyclic retinoid induces partial differentiation, down-regulates telomerase reverse transcriptase mRNA expression and telomerase activity, and induces apotosis in human hepatoma-derived cell lines. 10 Studies were done for different inhibitors of telomerase reverse transcriptase in other disease conditions like boldine, 11 crocin, 12 dimethyl sulfoxide, 13 harmine, 14 helenalin, 15 pristimerin, 16 tanshinone, 17 triethylene tetraamine, 18 and tocotrienol. 19 .…”

Section: Discussionmentioning

confidence: 99%

In silico prediction of telomerase reverse transcriptase inhibitors using modified retinol for the treatment of arsenical cancer

Tshering¹,

Misbahuddin²

2016

Bangabandhu Sheikh Mujib Medical University Journal

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<p align="left">Retinol molecule was modified to predict the inhibitors of telomerase reverse transcriptase for the treatment of arsenical cancer through <em>in silico</em> study. Telomerase activity is expressed in the cancerous conditions which can be the target for anticancer activity by inhibiting telomerase reverse transcriptase enzyme. The inhibitors were predicted through molecular docking of modified retinol with telomerase reverse transcriptase. Taking into account of low binding energy and high binding affinity two new compounds, compound number 606 and compound number 609 were predicted as the inhibitors of telomerase reverse transcriptase for the treatment of arsenical cancer. The prediction of these two compounds was further supported by drug-likeness test through Administration, Distribution, Metabolism, Excretion and Toxicity evaluation. The compounds were also compared with some of the known inhibitors of telomerase reverse transcriptase. </p>

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“…Helenalin potently inhibits human telomerase, an enzyme activated in most cancer cells [130,131]. The inhibition has been attributed to alkylation of cystein-445 residue of telomerase [132]. A pulchellin derivative designated P13 (2-desoxy-4β-propylcarbamate-pulchellin, Figure 8) was found to bind covalently to cytsein-452 of Janus kinase 2 (JAK2), a key kinase implicated in STAT3 signaling [133].…”

Section: Thiol Reactivitymentioning

confidence: 99%

Anticancer Targets and Signaling Pathways Activated by Britannin and Related Pseudoguaianolide Sesquiterpene Lactones

Bailly

2021

Biomedicines

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Sesquiterpene lactones (SLs) are abundant in plants and display a large spectrum of bioactivities. The compound britannin (BRT), found in different Inula species, is a pseudoguaianolide-type SL equipped with a typical and highly reactive α-methylene-γ-lactone moiety. The bioproperties of BRT and related pseudoguaianolide SLs, including helenalin, gaillardin, bigelovin and others, have been reviewed. Marked anticancer activities of BRT have been evidenced in vitro and in vivo with different tumor models. Three main mechanisms are implicated: (i) interference with the NFκB/ROS pathway, a mechanism common to many other SL monomers and dimers; (ii) blockade of the Keap1-Nrf2 pathway, with a covalent binding to a cysteine residue of Keap1 via the reactive α-methylene unit of BRT; (iii) a modulation of the c-Myc/HIF-1α signaling axis leading to a downregulation of the PD-1/PD-L1 immune checkpoint and activation of cytotoxic T lymphocytes. The non-specific reactivity of the α-methylene-γ-lactone moiety with the sulfhydryl groups of proteins is discussed. Options to reduce or abolish this reactivity have been proposed. Emphasis is placed on the capacity of BRT to modulate the tumor microenvironment and the immune-modulatory action of the natural product. The present review recapitulates the anticancer effects of BRT, some central concerns with SLs and discusses the implication of the PD1/PD-L1 checkpoint in its antitumor action.

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The inhibitory effect of helenalin on telomerase activity is attributed to the alkylation of the CYS445 residue: Evidence from QM/MM simulations

Cited by 8 publications

References 44 publications

Discovery and Computational Studies of Potent Covalent Kinase Inhibitors with α-Substituent Electrophiles Targeting Cysteine

Discovery and Computational Studies of Potent Covalent Kinase Inhibitors with α-Substituent Electrophiles Targeting Cysteine

In silico prediction of telomerase reverse transcriptase inhibitors using modified retinol for the treatment of arsenical cancer

Anticancer Targets and Signaling Pathways Activated by Britannin and Related Pseudoguaianolide Sesquiterpene Lactones

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