Inhibition of Dihydrofolate Reductase and Cell Growth by Antifolates in a Methotrexate-Resistant Cell Line

Hamrell, Michael R.

doi:10.1159/000225851

Cited by 6 publications

(4 citation statements)

References 3 publications

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“…The structural requirements for potential DHFR inhibitors are summarized in recent review articles. − The availability of high resolution crystal structures of Pneumocystis carinii DHFR and human DHFR has provided impetus in the use of rational drug design techniques for the development of highly potent and specific DHFR inhibitors. , Thus, DHFR antagonists have been extensively studied and are currently used for the treatment of cancer, , psoriasis, autoimmune diseases, − malaria, bacterial and fungal infections, and infections by opportunistic microorganisms associated with AIDS. − Such inhibitors have been classified according to their structures, classical and nonclassical. The former have a structure similar to folate, where they possess a ring which is generally a pteridine connected to an aryl group and a moiety of glutamate.…”

Section: Introductionmentioning

confidence: 99%

Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration

Tosso¹,

Andújar²,

Gutiérrez³

et al. 2013

J. Chem. Inf. Model.

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A molecular modeling study on dihydrofolate reductase (DHFR) inhibitors was carried out. By combining molecular dynamics simulations with semiempirical (PM6), ab initio, and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of DHFR inhibitors interacting with the human enzyme is reported here, providing a clear picture of the binding interactions of these ligands from both structural and energetic viewpoints. A reduced model for the binding pocket was used. This approach allows us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the quantum theory of atoms in molecules (QTAIM) technique. Thus, molecular aspects of the binding interactions between inhibitors and the DHFR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental IC₅₀ values was obtained, predicting with an acceptable qualitative accuracy the potential inhibitor effect of nonsynthesized compounds. Such correlation was experimentally corroborated synthesizing and testing two new inhibitors reported in this paper.

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Section: Introductionmentioning

confidence: 99%

Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration

Tosso¹,

Andújar²,

Gutiérrez³

et al. 2013

J. Chem. Inf. Model.

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“…Pharmacological studies using metoprine indicated that the activation of the histaminergic system in the CNS affects a wide variety of brain functions such as antinociception [79], suppression of energy intake [80], hyperglycaemic action [81], improvement of cognitive function [82], antiepileptic effect [83,84,85], and attenuation of methamphetamine-induced behavioural abnormalities [86]. However, metoprine can also inhibit mammalian dihydrofolate reductase (EC 1.5.1.3) and decrease cellular folate metabolism, resulting in the attenuation of cell growth [87,88]; therefore, it cannot be ruled out that the low specificity of metoprine affected the results. Another HNMT inhibitor, SKF91488, developed by Beaven et al can specifically inhibit the enzymatic activity devoid of histamine receptor agonist activity [89].…”

Section: Pharmacological Analysis Using Hnmt Inhibitorsmentioning

confidence: 99%

Histamine N-Methyltransferase in the Brain

Yoshikawa

Nakamura

Yanai

2019

IJMS

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Brain histamine is a neurotransmitter and regulates diverse physiological functions. Previous studies have shown the involvement of histamine depletion in several neurological disorders, indicating the importance of drug development targeting the brain histamine system. Histamine N-methyltransferase (HNMT) is a histamine-metabolising enzyme expressed in the brain. Although pharmacological studies using HNMT inhibitors have been conducted to reveal the direct involvement of HNMT in brain functions, HNMT inhibitors with high specificity and sufficient blood–brain barrier permeability have not been available until now. Recently, we have phenotyped Hnmt-deficient mice to elucidate the importance of HNMT in the central nervous system. Hnmt disruption resulted in a robust increase in brain histamine concentration, demonstrating the essential role of HNMT in the brain histamine system. Clinical studies have suggested that single nucleotide polymorphisms of the human HNMT gene are associated with several brain disorders such as Parkinson’s disease and attention deficit hyperactivity disorder. Postmortem studies also have indicated that HNMT expression is altered in human brain diseases. These findings emphasise that an increase in brain histamine levels by novel HNMT inhibitors could contribute to the improvement of brain disorders.

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“…Because of their distinct pharmacological and physicochemical properties compared to MTX, new antifolate compounds are being investigated for use against MTX-resistant cells (Burchenal et al 1952;Mishra et al 1973;Ho et al 1972;Nichol et al 1977). The use of these classes of analogs to increase selectivity and overcome the issue of MTX-resistant cells has gotten a lot of attention (Hamrell 1984). B-cell lymphoma-2 (BCL-2) is the name given to an unidentified gene found in follicular lymphoma (Tsujimoto et al 1985).…”

Section: Introductionmentioning

confidence: 99%

Prospect into therapeutic potentials of Moringa oleifera phytocompounds against cancer upsurge: de novo synthesis of test compounds, molecular docking, and ADMET studies

et al. 2021

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Background Cancer chemotherapy is difficult because current medications for the treatment of cancer have been linked to a slew of side effects; as a result, researchers are tasked with developing greener cancer chemotherapies. Moringa oleifera has been reported with several bioactive compounds which confirm its application for various ailments by traditional practitioners. In this study, we aim to prospect the therapeutic potentials of M. oleifera phytocompounds against cancer proliferation as a step towards drug discovery using a computational approach. Target proteins: dihydrofolate reductase (DHFR) and B-Cell Lymphoid-2 (BCL-2), were retrieved from the RCSB PDB web server. Sixteen and five phytocompounds previously reported in M. oleifera leaves (ML) and seeds (MS), respectively, by gas chromatography–mass spectrometry were synthesized and used in the molecular docking study. For accurate prediction of binding sites of the target proteins; standard inhibitors, Methotrexate (MTX) for DHFR, and Venetoclax (VTC) for BCL-2, were docked together with the test compounds. We further predicted the ADMET profile of the potential inhibitors for an insight into their chance of success as candidates in drug discovery. Results Results for the binding affinities, docking poses, and the interactions showed that ML2, ML4-6, ML8-15, and MS1-5 are potential inhibitors of DHFR and BCL-2, respectively. In the ADMET profile, ML2 and ML4 showed the best drug-likeness by non-violation of Lipski Rule of Five. ML4-6, ML8, ML11, ML14-15, and MS1, MS3-5 exhibit high GI absorption; ML2, ML4-6, ML8, MS1, and MS5 are blood–brain barrier permeants. ML2, ML4, ML9, ML13, and MS2 do not interfere with any of the CYP450 isoforms. The toxicity profile showed that all the potential inhibitors are non-carcinogenic and non-hERG I (human ether-a-go-go related gene I) inhibitors. ML4, ML11, and MS4 are hepatotoxic and ML7, ML10, and MS4 are hERG II inhibitors. A plethora of insights on the toxic endpoints and lethal concentration values showed that ML5, ML13, and MS2 are comparatively less lethal than other potential inhibitors. Conclusion This study has demonstrated that M. oleifera phytocompounds are potential inhibitors of the disease proteins involved in cancer proliferation, thus, an invaluable step toward the discovery of cancer chemotherapy with lesser limitations.

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Inhibition of Dihydrofolate Reductase and Cell Growth by Antifolates in a Methotrexate-Resistant Cell Line

Cited by 6 publications

References 3 publications

Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration

Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration

Histamine N-Methyltransferase in the Brain

Prospect into therapeutic potentials of Moringa oleifera phytocompounds against cancer upsurge: de novo synthesis of test compounds, molecular docking, and ADMET studies

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