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Computers in Biology and Medicine Jul 2022GLS1 enzymes (Glutaminase C (GAC) and kidney-type Glutaminase (KGA)) are gaining prominence as a target for tumor treatment including lung, breast, kidney, prostate, and...
GLS1 enzymes (Glutaminase C (GAC) and kidney-type Glutaminase (KGA)) are gaining prominence as a target for tumor treatment including lung, breast, kidney, prostate, and colorectal. To date, several medicinal chemistry studies are being conducted to develop new and effective inhibitors against GLS1 enzymes. Telaglenastat, a drug that targets the allosteric site of GLS1, has undergone clinical trials for the first time for the therapy of solid tumors and hematological malignancies. A comprehensive computational investigation is performed to get insights into the inhibition mechanism of the Telaglenastat. Some novel inhibitors are also proposed against GLS1 enzymes using the drug repurposing approach using 2D-fingerprinting virtual screening method against 2.4 million compounds, application of pharmacokinetics, Molecular Docking, and Molecular Dynamic (MD) Simulations. A TIP3P water box of 10 Å was defined to solvate both enzymes to improve MD simulation reliability. The dynamics results were validated further by the MMGB/PBSA binding free energy method, RDF, and AFD analysis. Results of these computational analysis revealed a stable binding affinity of Telaglenastat, as well as an FDA approved drug Astemizole (IC ∼ 0.9 nM) and a novel para position oriented methoxy group containing Chembridge compound (Chem-64284604) that provides an effective inhibitory action against GAC and KGA.
Topics: Humans; Male; Cell Line, Tumor; Drug Repositioning; Enzyme Inhibitors; Glutaminase; Molecular Docking Simulation; Molecular Dynamics Simulation; Reproducibility of Results
PubMed: 35654625
DOI: 10.1016/j.compbiomed.2022.105669 -
The Journal of Pharmacology and... Aug 2022Infigratinib (INF) is a fibroblast growth factor receptor inhibitor that was recently United States Food and Drug Administration-approved for the treatment of advanced...
Identification of Infigratinib as a Potent Reversible Inhibitor and Mechanism-Based Inactivator of CYP2J2: Nascent Evidence for a Potential In Vivo Metabolic Drug-Drug Interaction with Rivaroxaban.
Infigratinib (INF) is a fibroblast growth factor receptor inhibitor that was recently United States Food and Drug Administration-approved for the treatment of advanced or metastatic cholangiocarcinoma. We previously established that INF inhibited and inactivated cytochrome P450 3A4 (CYP3A4). Here, in a follow up to our previous study, we identified for the first time that INF also elicited potent competitive inhibition and mechanism-based inactivation of CYP2J2 with kinetic parameters , , , and a partition ratio of 1.94 M, 0.10 M, 0.026 minute, and ∼3, respectively, when rivaroxaban was harnessed as the probe substrate. Inactivation was revealed to exhibit cofactor-dependency and was attenuated by an alternative substrate (astemizole) and direct inhibitor (nilotinib) of CYP2J2. Additionally, the nature of inactivation was unlikely to be pseudo-irreversible and instead arose from covalent modification due to the lack of substantial enzyme activity recovery after dialysis and chemical oxidation, as well as the lack of a resolvable Soret band in spectral scans. Glutathione trapping confirmed that the identity of the putative reactive intermediate implicated in the covalent inactivation of both CYP2J2 and CYP3A4 was identical and likely attributable to an electrophilic -benzoquinonediimine intermediate of INF. Finally, mechanistic static modeling revealed that by integrating the previously arcane inhibition and inactivation kinetic parameters of CYP2J2-mediated rivaroxaban hydroxylation by INF illuminated in this work, together with those previously documented for CYP3A4, a 49% increase in the systemic exposure of rivaroxaban was projected. Our modeling results predicted a potential risk of metabolic drug-drug interactions between the clinically relevant combination of rivaroxaban and INF in the setting of cancer. SIGNIFICANCE STATEMENT: This study reported that INF elicits potent reversible inhibition and mechanism-based inactivation of CYP2J2. Furthermore, static modelling predicted that its coadministration with the direct oral anticoagulant rivaroxaban may potentially culminate in a metabolic drug-drug interaction (DDI) leading to an increased risk of major bleeding. As rivaroxaban is steadily gaining prominence as the anticoagulant of choice in the treatment of cancer-associated venous thromboembolism, the DDI projections reported here are clinically relevant and warrant further investigation via physiologically based pharmacokinetic modelling and simulation.
Topics: Anticoagulants; Cytochrome P-450 CYP2J2; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Phenylurea Compounds; Pyrimidines; Rivaroxaban
PubMed: 35640957
DOI: 10.1124/jpet.122.001222 -
Annals of Medicine and Surgery (2012) Jun 2022Cardiac toxicity is a very seldom documented side effect of Pheniramine. Although second-generation antihistamines such as terfenadine and astemizole have been linked to...
Cardiac toxicity is a very seldom documented side effect of Pheniramine. Although second-generation antihistamines such as terfenadine and astemizole have been linked to cardiac injury, the incidence of SVT after Pheniramine treatment on adult clinical dose is currently unknown. In this case, we present a 22-year-old girl who developed adenosine-resistant supraventricular tachycardia (SVT) after being given pheniramine due to a bean allergy. It is crucial to know that symptomatic SVT could occur with therapeutic doses of pheniramine. This case highlights the importance of a comprehensive drug evaluation in emergency situations to identify the underlying etiologies and prompt treatment commencement. It also emphasizes the significance of assessing and choosing acute drugs for each patient admitted to the emergency unit to ensure the start of a newer medication if necessary.
PubMed: 35600167
DOI: 10.1016/j.amsu.2022.103621 -
European Journal of Medicinal Chemistry Jun 2022The development of inhibitors of key biological mechanisms involved in multidrug resistance (MDR) burden meets an important medical need but still represents a... (Review)
Review
The development of inhibitors of key biological mechanisms involved in multidrug resistance (MDR) burden meets an important medical need but still represents a challenging task. Major MDR targets in both bacterial and cancer cells are multidrug efflux systems. Several aspects should be considered in the attempt to design efficient inhibitors of these systems such as toxicity, stability, permeability as a few examples. In order to successfully design promising new compounds, a full understanding of the efflux mechanism is required, from both biological and structural points of view. It is nowadays well established that the success rate in classical drug design and biological evaluation improves when combined with in silico methodologies. In this review, we focus on the biological evaluation and molecular mechanistic insights of inhibitors of the drug efflux activity of the Hedgehog receptor Patched1 (Ptch1). Ptch1 is known to be over-expressed in many types of cancers, but its activity and role in the resistance to chemotherapy of cancer cells have been highlighted only recently. Remarkably, due to its peculiar efflux mechanism, inhibition of Ptch1 was shown to be particularly relevant for improving the efficacy of chemotherapy without concomitant toxicity for healthy cells or potential side effects. To date, three compounds have been identified as efficient Ptch1 inhibitors, namely astemizole, methiothepin and panicein A hydroquinone. Due to the chemical and structural differences of these molecules, the hit-to-lead drug design is not straightforward. This review describes how the merging of in vitro, in vivo and in silico studies provides molecular details that could contribute to the rational design of new Ptch1 inhibitors.
Topics: Drug Design; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Hedgehog Proteins; Humans; Neoplasms; Patched-1 Receptor
PubMed: 35421658
DOI: 10.1016/j.ejmech.2022.114306 -
Methods in Molecular Biology (Clifton,... 2022Human ether-a-go-go-related gene (hERG) channel plays an essential role in the repolarization of the cardiac action potential. Genetic mutations and some chemicals/drugs...
Human ether-a-go-go-related gene (hERG) channel plays an essential role in the repolarization of the cardiac action potential. Genetic mutations and some chemicals/drugs interfere with hERG channel activity, which may prolong the QT interval and potentially cause long QT syndrome. The FluxOR™ thallium flux assay performed in two cell lines, U2OS and HEK293, with stable hERG expression can be used to identify compounds that inhibit hERG channel activity. This chapter describes a cell-based hERG channel inhibition assay that has been optimized and performed in a 1536-well plate format. The homogeneous and robust assay can be used to identify compounds that inhibit hERG channel activity.
Topics: Action Potentials; Ether-A-Go-Go Potassium Channels; HEK293 Cells; Humans; Long QT Syndrome; Research Design
PubMed: 35294752
DOI: 10.1007/978-1-0716-2213-1_3 -
Current Organic Synthesis 2023Benzimidazole (BI) and its derivatives are interesting molecules in medicinal chemistry because several of these compounds have a diversity of biological activities and... (Review)
Review
Benzimidazole (BI) and its derivatives are interesting molecules in medicinal chemistry because several of these compounds have a diversity of biological activities and some of them are even used in clinical applications. In view of the importance of these compounds, synthetic chemists are still interested in finding new procedures for the synthesis of these classes of compounds. Astemizole (antihistaminic), Omeprazole (antiulcerative), and Rabendazole (fungicide) are important examples of compounds used in medicinal chemistry containing BI nuclei. It is interesting to observe that several of these compounds contain 2-aminobenzimidazole (2ABI) as the base nucleus. The structures of 2ABI derivatives are interesting because they have a planar delocalized structure with a cyclic guanidine group, which have three nitrogen atoms with free lone pairs and labile hydrogen atoms. The 10-π electron system of the aromatic BI ring conjugated with the nitrogen lone pair of the hexocyclic amino group, making these heterocycles to have an amphoteric character. Synthetic chemists have used 2ABI as a building block to produce BI derivatives as medicinally important molecules. In view of the importance of the BIs, and because no review was found in the literature about this topic, we reviewed and summarized the procedures related to the recent methodologies used in the N-substitution reactions of 2ABIs by using aliphatic and aromatic halogenides, dihalogenides, acid chlorides, alkylsulfonic chlorides, carboxylic acids, esters, ethyl chloroformates, anhydrides, SMe-isothioureas, alcohols, alkyl cyanates, thiocyanates, carbon disulfide and aldehydes or ketones to form Schiff bases. The use of diazotized 2ABI as intermediate to obtain 2-diazoBIs was included to produce Nsubstituted 2ABIs of pharmacological interest. Some commentaries about their biological activity were included.
Topics: Pharmacophore; Benzimidazoles; Aldehydes; Nitrogen
PubMed: 35272598
DOI: 10.2174/1570179419666220310124223 -
Se Pu = Chinese Journal of... Mar 2022An accurate mass database and a method based on ultra high performance liquid chromatography-electrostatic field orbitrap high resolution mass spectrometry...
[Rapid screening and identification of 167 illegally added medicines in herbal tea by ultra high performance liquid chromatography-electrostatic field orbitrap high resolution mass spectrometry].
An accurate mass database and a method based on ultra high performance liquid chromatography-electrostatic field orbitrap high resolution mass spectrometry (UHPLC-Orbitrap HRMS) were developed. These were applied in the screening and identification of illegally added medicines in herbal tea. Based on investigations, 167 medicines were selected to build an accurate MS database; these medicines included antipyretic analgesics, glucocorticoids, antibiotics, and antihistamines, among other categories. The database was established using Orbitrap HRMS and TraceFinder software. The database carried information on all selected compounds, including the molecular formula, accurate mass of precursor ions and fragment ions, retention time, and mass spectra. The samples were ultrasonically extracted with a 50% (v/v) methanol aqueous solution. The extracted solutions were separated using a Waters XBrigde BEH C18 column (100 mm×2.1 mm, 2.5 μm). As the mobile phases, 0.1% (v/v) formic acid aqueous solution and acetonitrile containing 0.1% (v/v) formic acid were used, with gradient elution. The sample solutions were analyzed by Orbitrap HRMS in the full-scan MS and data-dependent MS/MS acquisition modes (Full MS/dd-MS). Positive and negative polarity data were simultaneously acquired. Some parameters were optimized to increase the peak intensity and sensitivity of all compounds. The resolutions in the full-MS scan and dd-MS scan were set to 70000 and 17500, respectively. In the full-MS mode, scanning was performed in the range of m/z 100 to 1000. In the MS/MS mode, the normalized collision energy (NEC) was set to 20%, 40%, and 60% for each compound. The inclusion list was not used during the measurement, and the dynamic exclusion time was set to 10.0 s. The loop count was set to 5. After acquiring the sample data with these conditions using Orbitrap MS, they were imported into TraceFinder software, through which the sample information was extracted and automatically matched with the information on compounds in the MS database. Screening and identification were conducted by comparing the retention times as well as the exact masses of precursor ions and fragment ions that were experimentally measured. If the errors between the experimentally and theoretically obtained masses of the precursor ions were below 5×10 and the deviations in retention times were less than 20 s, then suspicious positive compounds might be identified. Furthermore, if such compounds possess more than one similar fragment ion with a mass tolerance below 5×10, and exhibit similar ion distributions in the MS/MS profiles (compared to those in the database), they could be confirmed to be the same. The validation result showed that all compounds had good linear relationships, with correlation coefficients (r) greater than 0.99. Because pefloxacin, norfloxacin, desloratadine, astemizole and clindamycin had background interference, the method was not suitable for their quantification. Following experiments using three spiked concentrations, the recoveries of the rest 162 compounds were found to be in the range of 66.4%-118.1%, and the relative standard deviations (RSDs, n=6), in the range of 0.1%-16.1%. When the limit of detection (LOD) was 0.2 mg/kg, 83 compounds were detected, while when the LOD was 1.0 mg/kg, 167 compounds were detected. All compounds were matched successfully to the standard added sample with the MS database in TraceFinder software. To lower the likelihood of false positive and false negative results, a quality control method was recommended. The method was applied to analyze 245 herbal tea samples, among which 12 positive samples were detected. Thirteen positive compounds were found, including acetaminophen, diclofenac sodium, chlorpheniramine, brompheniramine, dexamethasone, dexamethasone 21-acetate, prednisone, prednisone 21-acetate, metronidazole, erythromycin, ciprofloxacin, amantadine, and dextromethorphan. In particular, amantadine, dextromethorphan, brompheniramine, and ciprofloxacin were newly detected, compared to standard methods. The developed method is rapid and accurate, and will be useful in the high-throughput screening of illegally added medicines in herbal tea.
Topics: Chromatography, High Pressure Liquid; Limit of Detection; Static Electricity; Tandem Mass Spectrometry; Teas, Herbal
PubMed: 35243835
DOI: 10.3724/SP.J.1123.2021.07006 -
International Journal of Molecular... Dec 2021Apicomplexan parasites, such as , spp., spp., and spp., cause significant morbidity and mortality. Existing treatments are problematic due to toxicity and the...
Apicomplexan parasites, such as , spp., spp., and spp., cause significant morbidity and mortality. Existing treatments are problematic due to toxicity and the emergence of drug-resistant parasites. Because protozoan tubulin can be selectively disrupted by small molecules to inhibit parasite growth, we assembled an in vitro testing cascade to fully delineate effects of candidate tubulin-targeting drugs on and vertebrate host cells. Using this analysis, we evaluated clemastine, an antihistamine that has been previously shown to inhibit growth by competitively binding to the CCT/TRiC tubulin chaperone as a proof-of-concept. We concurrently analyzed astemizole, a distinct antihistamine that blocks heme detoxification in . Both drugs have EC values of ~2 µM and do not demonstrate cytotoxicity or vertebrate microtubule disruption at this concentration. Parasite subpellicular microtubules are shortened by treatment with either clemastine or astemizole but not after treatment with pyrimethamine, indicating that this effect is not a general response to antiparasitic drugs. Immunoblot quantification indicates that the total α-tubulin concentration of 0.02 pg/tachyzoite does not change with clemastine treatment. In conclusion, the testing cascade allows profiling of small-molecule effects on both parasite and vertebrate cell viability and microtubule integrity.
Topics: Animals; Antiparasitic Agents; Apicoplasts; Cells, Cultured; Clemastine; Histamine Antagonists; Humans; Microtubules; Parasites; Protozoan Proteins; Tubulin
PubMed: 35008492
DOI: 10.3390/ijms23010068 -
Biochemical and Biophysical Research... Jan 2022Distinct macrophage populations exert highly heterogeneity and perform various functions, among which, a crucial function of lipid metabolism is highlighted. However,...
Distinct macrophage populations exert highly heterogeneity and perform various functions, among which, a crucial function of lipid metabolism is highlighted. However, the role of histidine metabolism disorder in macrophage lipid metabolism remains elusive. Addressed this question, we sorted and cultured the bone marrow-derived macrophages (BMDMs) of histidine decarboxylase (Hdc) knockout (Hdc) mice with an in vitro oxidized low-density lipoprotein (ox-LDL) model, and detected the intracellular lipids by Oil Red O staining as well as lipid probe staining. Astemizole, a canonical and long-acting histamine H receptor (HR) antagonist, was applied to elucidate the impact of antagonizing the HR-dependent signaling pathway on macrophage lipid metabolism. Subsequently, the differential expressed genes were screened and analyzed in the bone marrow-derived CD11b immature myeloid cells of Hdc and Hdc mice with a high fat diet by the microarray study. The expression levels of cholesterol metabolism-related genes were examined by qRT-PCR to explore underlying mechanisms. Lastly, we used a high-sensitivity histidine probe to detect the intracellular histidine in the BMDMs after oxidative stress. The results revealed that histidine metabolism disorder and histamine deficiency aggravated lipid accumulation in the ox-LDL-treated BMDMs. The expression level of HR gene in the BMDMs was down-regulated after ox-LDL stimulation. The disruption of the HR-dependent signaling pathway by astemizole further exacerbated ox-LDL-induced lipid deposition in the BMDMs partly by up-regulating scavenger receptor class A (SR-A) for lipid intake, down-regulating neutral cholesteryl ester hydrolase (nCEH) for cholesterol esterification and down-regulating ATP-binding cassette transporters A1 (ABCA1) and ABCG1 for reverse cholesterol transport. The intracellular histidine increased under ox-LDL condition, which was further increased by Hdc knockout. Collectively, these results partially reveal the relationship between histidine metabolism and lipid metabolism in the BMDMs and offer a novel strategy for lipid metabolism disorder-associated diseases.
Topics: Animals; Cholesterol; Gene Expression Profiling; Gene Expression Regulation; Histamine; Histidine; Lipid Metabolism; Lipoproteins, LDL; Macrophages; Male; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Histamine; Signal Transduction; Mice
PubMed: 34954523
DOI: 10.1016/j.bbrc.2021.12.069 -
Microsystems & Nanoengineering 2021Cardiovascular disease (CVD) is the number one cause of death in humans. Arrhythmia induced by gene mutations, heart disease, or hERG K channel inhibitors is a serious...
Cardiovascular disease (CVD) is the number one cause of death in humans. Arrhythmia induced by gene mutations, heart disease, or hERG K channel inhibitors is a serious CVD that can lead to sudden death or heart failure. Conventional cardiomyocyte-based biosensors can record extracellular potentials and mechanical beating signals. However, parameter extraction and examination by the naked eye are the traditional methods for analyzing arrhythmic beats, and it is difficult to achieve automated and efficient arrhythmic recognition with these methods. In this work, we developed a unique automated template matching (ATM) cardiomyocyte beating model to achieve arrhythmic recognition at the single beat level with an interdigitated electrode impedance detection system. The ATM model was established based on a rhythmic template with a data length that was dynamically adjusted to match the data length of the target beat by spline interpolation. The performance of the ATM model under long-term astemizole, droperidol, and sertindole treatment at different doses was determined. The results indicated that the ATM model based on a random rhythmic template of a signal segment obtained after astemizole treatment presented a higher recognition accuracy (100% for astemizole treatment and 99.14% for droperidol and sertindole treatment) than the ATM model based on arrhythmic multitemplates. We believe this highly specific ATM method based on a cardiomyocyte beating model has the potential to be used for arrhythmia screening in the fields of cardiology and pharmacology.
PubMed: 34567738
DOI: 10.1038/s41378-021-00251-4