Zeitschriftenartikel: „POTENTIAL INHIBITORS“

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Lechner, Christian, Maren Flaßhoff, Hannes Falke, Lutz Preu, Nadége Loaëc, Laurent Meijer, Stefan Knapp, Apirat Chaikuad und Conrad Kunick. „[b]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors“. Molecules 24, Nr. 22 (13.11.2019): 4090. http://dx.doi.org/10.3390/molecules24224090.

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Since hyperactivity of the protein kinase DYRK1A is linked to several neurodegenerative disorders, DYRK1A inhibitors have been suggested as potential therapeutics for Down syndrome and Alzheimer’s disease. Most published inhibitors to date suffer from low selectivity against related kinases or from unfavorable physicochemical properties. In order to identify DYRK1A inhibitors with improved properties, a series of new chemicals based on [b]-annulated halogenated indoles were designed, synthesized, and evaluated for biological activity. Analysis of crystal structures revealed a typical type-I binding mode of the new inhibitor 4-chlorocyclohepta[b]indol-10(5H)-one in DYRK1A, exploiting mainly shape complementarity for tight binding. Conversion of the DYRK1A inhibitor 8-chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one into a corresponding Mannich base hydrochloride improved the aqueous solubility but abrogated kinase inhibitory activity.

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Sharma, Manish Kumar, Anil Kumar Sharma und S. P. Mathur. „Solanum surrattence as Potential Corrosion Inhibitor“. ISRN Corrosion 2012 (28.08.2012): 1–5. http://dx.doi.org/10.5402/2012/907676.

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Developping chip and ecofriendlly corrosion inhibitors can replace toxic chemicals which are currently used in industries. Plant extract of Solanum surrattence in acetone, petroleum ether, and methanol has been tasted using mass loss and thermometric measurements for corrosion of aluminium in acid solutions. The plant extract of Solanum surrattence is a good corrosion inhibitor for aluminium. The inhibition efficiency depends upon the concentration of inhibitors, it inhibits the metal of 97.60% at its maximum value. This inhibitor shows efficiency at 25°C. At higher temperature the inhibition efficiency decreases. These types of inhibitors can be used to replace the toxic chemicals which are currently used in industries. We find out cheap and ecofriendlly corrosion inhibitors which can be used by acid, petrochemical, and chemical industries.

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Samsudin, Sity Juaeiriah, Nurlidia Binti Mansor, Suriati Sufian und Zakaria B. Man. „The Potential of Garlic Extract as Bio-Inhibitor in Urea Fertilizer“. Key Engineering Materials 594-595 (Dezember 2013): 296–300. http://dx.doi.org/10.4028/www.scientific.net/kem.594-595.296.

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Urea is extensively used as fertilizer in the agricultural industry based on its suitability for all types of crops. The hydrolysis of urea fertilizer produces ammonia (NH3) and carbon dioxide (CO2). However, up to 40% of NH3 release affects the efficiency of urea fertilizer. By introducing inhibitors into the urea enzymatic reaction, the NH3 emission problem can be solved. Unfortunately, current inhibitors are usually chemical based and non-biodegradable. Several complaints and accidents have been reported when handling chemical based inhibitors especially for surface application. Research on garlic or Allium savatium has been conducted to ensure its inhibitory effects as potentially safe and biodegradable inhibitor. From previous research, thiosulfinates (TS) contained in garlic extract proved to inhibit platelets aggregation in medical applications. In this study, the inhibitory effect is determined by analyzing NH3 concentration in urease-garlic mixture and standard urea assay mixtures using UV-VIS spectrophotometer device. Previous research showed the highest absorbance of free NH3 was detected at 370nm. At 30 minutes of 15ml of urease-garlic mixture confirms the fully inhibition of garlic extract towards reaction.

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Buolamwini, John K. „Nucleoside Transport Inhibitors: Structure-Activity Relationships and Potential Therapeutic Applications“. Current Medicinal Chemistry 4, Nr. 1 (Februar 1997): 35–66. http://dx.doi.org/10.2174/0929867304666220309201038.

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A survey of structure-activity relationships and potential therapeutic applications of nucleoside transport inhibitors is presented. Among the two equilibrative (facilitated diffusion), and five concentrative (sodium-dependent) nucleoside transporters identified in mammalian cells, only the equilibrative transporters (es and e1) and one concentrative transporter (cs) can be effectively blocked by one or more of the nucleoside transport inhibitors discovered to date. A structurally diverse array of compounds have been shown to exert nucleoside transport inhibitory activity to varying degrees. The most important of these are i) nucleoside analogs of which s6-(4-nitrobenzyl)mercaptopurine riboside (NBMPR, nitrobenzylthioinosine) is the prototype, ii) pyrimidopyrimidine and pteridine derivatives of which dipyridamole (Persantine) is the prototype, and iii) alkyl- and cycloalkyldiamine and piperazine calcium channel antagonists of which dilazep and lidoflazine are the representatives, respectively. All of these are effective inhibitors of the es transporter, but dipyridamole is also a potent inhibitor of the ei transporter with variable activity depending on the cell type. Surprisingly, NBMPR and dipyridamole are also potent inhibitors of the newly identified cs concentrative transporter in fresh leukemia cells from patients. Not only does the es inhibitory potency of these compounds depend on tissue type, but it also varies widely among different mammalian species. <p> Nucleoside transport inhibitors have potential for therapeutic uses in 1) adenosine potentiation in cardioprotection and cerebroprotection in ischemic heart disease and stroke, respectively, 2) the modulation of the effects of antimetabolite anticancer and antiviral agents, and 3) host tissue protection in chemotherapy with cytotoxic nucleosides. Additional areas of potential therapeutic application of NT inhibitors include kidney transplantation, analgesia and hypertension. Most of the compounds in the present repertoire of potent NT inhibitors do not meet the requisite pharmacological profiles for successful clinical application, which calls for the discovery of better inhibitors. Advances are being made in the molecular cloning and functional expression of nucleoside transporters that augur well for future drug design efforts. </p>

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Chen, Xingchen, Darren Leahy, Jessica Van Haeften, Perry Hartfield, Peter J. Prentis, Chloé A. van der Burg, Joachim M. Surm et al. „A Versatile and Robust Serine Protease Inhibitor Scaffold from Actinia tenebrosa“. Marine Drugs 17, Nr. 12 (12.12.2019): 701. http://dx.doi.org/10.3390/md17120701.

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Serine proteases play pivotal roles in normal physiology and a spectrum of patho-physiological processes. Accordingly, there is considerable interest in the discovery and design of potent serine protease inhibitors for therapeutic applications. This led to concerted efforts to discover versatile and robust molecular scaffolds for inhibitor design. This investigation is a bioprospecting study that aims to isolate and identify protease inhibitors from the cnidarian Actinia tenebrosa. The study isolated two Kunitz-type protease inhibitors with very similar sequences but quite divergent inhibitory potencies when assayed against bovine trypsin, chymostrypsin, and a selection of human sequence-related peptidases. Homology modeling and molecular dynamics simulations of these inhibitors in complex with their targets were carried out and, collectively, these methodologies enabled the definition of a versatile scaffold for inhibitor design. Thermal denaturation studies showed that the inhibitors were remarkably robust. To gain a fine-grained map of the residues responsible for this stability, we conducted in silico alanine scanning and quantified individual residue contributions to the inhibitor’s stability. Sequences of these inhibitors were then used to search for Kunitz homologs in an A. tenebrosa transcriptome library, resulting in the discovery of a further 14 related sequences. Consensus analysis of these variants identified a rich molecular diversity of Kunitz domains and expanded the palette of potential residue substitutions for rational inhibitor design using this domain.

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Žbulj, Katarina, Gordana Bilić, Lidia Hrnčević und Katarina Simon. „Potential of using plant extracts as green corrosion inhibitors in the petroleum industry“. Rudarsko-geološko-naftni zbornik 36, Nr. 5 (2021): 132–39. http://dx.doi.org/10.17794/rgn.2021.5.12.

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In this paper, preliminary studies of ten different plant extracts as potential corrosion inhibitors of carbon steel were examined. For each extract, the concentration range in which it shows anti-corrosion action was first determined, and then the most effective concentration was determined for each extract. The tests were performed in a brine solution saturated with CO2 at room temperature. The aim of this study was to isolate extracts with high effectiveness and subsequent electrochemical and surface methods to determine the mechanism of inhibitory action. For this purpose, potentiodynamic polarization was performed with Tafel extrapolation. Among all the tested extracts, lady’s mantle (92.17%) and dandelion root (95.07%) stood out with their effectiveness. Both tested extracts showed the behaviour of a mixed corrosion inhibitor with a dominant influence on the anode process.

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Serio, Rosa, Flavia Mulé und Alessandra Postorino. „Noradrenergic, noncholinergic inhibitory junction potentials in rat proximal colon: role of nitric oxide“. Canadian Journal of Physiology and Pharmacology 73, Nr. 1 (01.01.1995): 79–84. http://dx.doi.org/10.1139/y95-011.

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Using a single sucrose gap apparatus, experiments were performed to determine the involvement of nitric oxide (NO) in the generation of noradrenergic, noncholinergic (NANC) inhibitory junction potentials in circular muscle of rat proximal colon. Inhibitors of NO synthase, Nω-nitro-L-arginine and its methyl ester, reduced the amplitude of the electrically evoked inhibitory junction potentials, without affecting membrane resting potential. Such an effect was stereospecific and it was prevented by L-arginine but not by D-arginine. Sodium nitroprusside induced a tetrodotoxin-resistant hyperpolarization, which was not affected by NO synthase inhibitors. Aparnin reduced sodium nitroprusside induced hyperpolarization, as well as NANC inhibitory junction potentials, and α-chymotrypsin decreased the amplitude of electrical field stimulation evoked responses. Residual responses after NO synthase inhibitors or after α-chymotrypsin were further reduced by pretreatment with α-chymotrypsin or NO synthase inhibitors, respectively. These results suggest that, in rat colonic circular muscle, NO plays an important role in NANC inhibitory junction potential generation. However, another mechanism, peptidergic in nature, is also involved.Key words: nonadrenergic noncholinergic nerves, inhibitory junction potential, nitric oxide, rat colon.

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Sliskovic, Drago R., und Bharat K. Trivedi. „ACAT Inhibitors: Potential Anti-atherosclerotic Agents“. Current Medicinal Chemistry 1, Nr. 3 (Oktober 1994): 204–55. http://dx.doi.org/10.2174/092986730103220214163743.

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Abstract: The evolution of ACAT inhibitors •from purely hypocholestero lemic agents to potential anti-atherosclerdtic agents has occurred only recently.A large number of structurally diverse ACAT inhibitors were initially developed as hypocholesterolemic agets whose prime mechanism of action was inhibition of dietary cholesterol absorption in the intestine, however, efficacy for such non-absorbable agents, in humans, has remained elusive. Esterification of cholesterol within the hepatocyte has been shown to be required for VLDL synthesis and secretion, and inhibition of ACAT within the artery wall may prove to be the "ultimate" anti-atherosclerotic mechanism by preventing the formation of cholesterol ester loaded macrophages (foam cells), the precursors of the fatty streak, an early lesion in the atherosclerotic process. Thus, more recently, there has been a concerted effort to design more bioavailable inhibitors capable of inhibiting the enzyme in the liver and artery wall. Displaying direct efficacy at the artery wall for an ACAT inhibitor has been complicated by the fact that in pre-clinical animal models, it has been difficult to dissociate the effects of lipid lowering from a true direct effect at the artery wall. Recently, a novel ACAT inhibitor, Cl-976, has been disclosed which displays anti-atherosclerotic activity in an injured cholesterol fed rabbit model of atherosclerosis without exhibiting a cholesterol lowering effect.The SAR around Cl-976 and related series will be discussed and placed in context with other novel structural types of ACAT inhibitors appearing in the recent literature.

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Robina, Inmaculada, Antonio Moreno-Vargas, Ana Carmona und Pierre Vogel. „Glycosidase Inhibitors as Potential HIV Entry Inhibitors?“ Current Drug Metabolism 5, Nr. 4 (01.08.2004): 329–61. http://dx.doi.org/10.2174/1389200043335513.

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Evans, Tarra, und Ursula Matulonis. „PARP inhibitors in ovarian cancer: evidence, experience and clinical potential“. Therapeutic Advances in Medical Oncology 9, Nr. 4 (03.02.2017): 253–67. http://dx.doi.org/10.1177/1758834016687254.

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Inhibitors of poly(ADP-ribose) polymerase (PARP) are considered one of the most active and exciting new therapies for the treatment of ovarian cancer. The anticancer activity of PARP inhibitors is based on the DNA repair vulnerability of many ovarian cancer cells, and multiple mechanisms of action of PARP inhibitors have been identified. As single agents, PARP inhibitors have demonstrated their greatest activity in ovarian cancer cells that harbor mutations in BRCA genes. Additionally, recent phase III studies have shown that single-agent PARP inhibitor activity extends beyond BRCA-related cancers and can benefit patients with ovarian cancers that do not have known BRCA mutations, especially when clinical characteristics such as platinum sensitivity and high-grade serous histology are present. PARP inhibitors have also been combined with chemotherapy, however, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations has hampered development of these combinations. Contrariwise, PARP inhibitor and biologic agent combinations, specifically antiangiogenic agents, appear well tolerated and show promising activity in both BRCA mutated ( BRCAm) and BRCA wild-type ( BRCAwt) cancers. Currently, multiple clinical trials are underway examining the antitumor activity of PARP inhibitor combination therapy.

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Shamkh, Israa M., Mohammed Al-Majidi, Ahmed Hassen Shntaif, Peter Tan Deng Kai, Ngoc Nh-Pham, Ishrat Rahman, Dalia Hamza et al. „Nontoxic and Naturally Occurring Active Compounds as Potential Inhibitors of Biological Targets in Liriomyza trifolii“. International Journal of Molecular Sciences 23, Nr. 21 (24.10.2022): 12791. http://dx.doi.org/10.3390/ijms232112791.

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In recent years, novel strategies to control insects have been based on protease inhibitors (PIs). In this regard, molecular docking and molecular dynamics simulations have been extensively used to investigate insect gut proteases and the interactions of PIs for the development of resistance against insects. We, herein, report an in silico study of (disodium 5′-inosinate and petunidin 3-glucoside), (calcium 5′-guanylate and chlorogenic acid), chlorogenic acid alone, (kaempferol-3,7-di-O-glucoside with hyperoside and delphinidin 3-glucoside), and (myricetin 3′-glucoside and hyperoside) as potential inhibitors of acetylcholinesterase receptors, actin, α-tubulin, arginine kinase, and histone receptor III subtypes, respectively. The study demonstrated that the inhibitors are capable of forming stable complexes with the corresponding proteins while also showing great potential for inhibitory activity in the proposed protein-inhibitor combinations.

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Tábi, Tamás, László Vécsei, Moussa B. Youdim, Peter Riederer und Éva Szökő. „Selegiline: a molecule with innovative potential“. Journal of Neural Transmission 127, Nr. 5 (27.09.2019): 831–42. http://dx.doi.org/10.1007/s00702-019-02082-0.

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Abstract Monoamine oxidase B (MAO-B) inhibitors have an established role in the treatment of Parkinson’s disease as monotherapy or adjuvant to levodopa. Two major recognitions were required for their introduction into this therapeutic field. The first was the elucidation of the novel pharmacological properties of selegiline as a selective MAO-B inhibitor by Knoll and Magyar and the original idea of Riederer and Youdim, supported by Birkmayer, to explore its effect in parkinsonian patients with on–off phases. In the 1960s, MAO inhibitors were mainly studied as potential antidepressants, but Birkmayer found that combined use of levodopa and various MAO inhibitors improved akinesia in Parkinson’s disease. However, the serious side effects of the first non-selective MAO inhibitors prevented their further use. Later studies demonstrated that MAO-B, mainly located in glial cells, is important for dopamine metabolism in the brain. Recently, cell and molecular studies revealed interesting properties of selegiline opening new possibilities for neuroprotective mechanisms and a disease-modifying effect of MAO-B inhibitors.

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Brown, Nancy J. „Review: Therapeutic potential of plasminogen activator inhibitor-1 inhibitors“. Therapeutic Advances in Cardiovascular Disease 4, Nr. 5 (26.07.2010): 315–24. http://dx.doi.org/10.1177/1753944710379126.

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Honisch, Claudia, Matteo Gazziero, Roberto Dallocchio, Alessandro Dessì, Davide Fabbri, Maria Antonietta Dettori, Giovanna Delogu und Paolo Ruzza. „Antamanide Analogs as Potential Inhibitors of Tyrosinase“. International Journal of Molecular Sciences 23, Nr. 11 (02.06.2022): 6240. http://dx.doi.org/10.3390/ijms23116240.

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The tyrosinase enzyme, which catalyzes the hydroxylation of monophenols and the oxidation of o-diphenols, is typically involved in the synthesis of the dark product melanin starting from the amino acid tyrosine. Contributing to the browning of plant and fruit tissues and to the hyperpigmentation of the skin, leading to melasma or age spots, the research of possible tyrosinase inhibitors has attracted much interest in agri-food, cosmetic, and medicinal industries. In this study, we analyzed the capability of antamanide, a mushroom bioactive cyclic decapeptide, and some of its glycine derivatives, compared to that of pseudostellarin A, a known tyrosinase inhibitor, to hinder tyrosinase activity by using a spectrophotometric method. Additionally, computational docking studies were performed in order to elucidate the interactions occurring with the tyrosinase catalytic site. Our results show that antamanide did not exert any inhibitory activity. On the contrary, the three glycine derivatives AG9, AG6, and AOG9, which differ from each other by the position of a glycine that substitutes phenylalanine in the parent molecule, improving water solubility and flexibility, showed tyrosinase inhibition by spectrophotometric assays. Analytical data were confirmed by computational studies.

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McFadden, Karyn, Patricia Fletcher, Fiorella Rossi, Kantharaju, Muddagowda Umashankara, Vanessa Pirrone, Srivats Rajagopal et al. „Antiviral Breadth and Combination Potential of Peptide Triazole HIV-1 Entry Inhibitors“. Antimicrobial Agents and Chemotherapy 56, Nr. 2 (14.11.2011): 1073–80. http://dx.doi.org/10.1128/aac.05555-11.

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ABSTRACTThe first stage of human immunodeficiency virus type 1 (HIV-1) infection involves the fusion of viral and host cellular membranes mediated by viral envelope glycoprotein gp120. Inhibitors that specifically target gp120 are gaining increased attention as therapeutics or preventatives to prevent the spread of HIV-1. One promising new group of inhibitors is the peptide triazoles, which bind to gp120 and simultaneously block its interaction with both CD4 and the coreceptor. In this study, we assessed the most potent peptide triazole, HNG-156, for inhibitory breadth, cytotoxicity, and efficacy, both alone and in combination with other antiviral compounds, against HIV-1. HNG-156 inhibited a panel of 16 subtype B and C isolates of HIV-1 in a single-round infection assay. Inhibition of cell infection by replication-competent clinical isolates of HIV-1 was also observed with HNG-156. We found that HNG-156 had a greater than predicted effect when combined with several other entry inhibitors or the reverse transcriptase inhibitor tenofovir. Overall, we find that HNG-156 is noncytotoxic, has a broad inhibition profile, and provides a positive combination with several inhibitors of the HIV-1 life cycle. These results support the pursuit of efficacy and toxicity analyses in more advanced cell and animal models to develop peptide triazole family inhibitors of HIV-1 into antagonists of HIV-1 infection.

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Yuasa, Hideya, Masayuki Izumi und Hironobu Hashimoto. „Thiasugars: Potential Glycosidase Inhibitors“. Current Topics in Medicinal Chemistry 9, Nr. 1 (01.01.2009): 76–86. http://dx.doi.org/10.2174/156802609787354270.

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Gao, Yinghong, Stephen P. Davies, Martin Augustin, Anna Woodward, Umesh A. Patel, Robert Kovelman und Kevin J. Harvey. „A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery“. Biochemical Journal 451, Nr. 2 (28.03.2013): 313–28. http://dx.doi.org/10.1042/bj20121418.

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Despite the development of a number of efficacious kinase inhibitors, the strategies for rational design of these compounds have been limited by target promiscuity. In an effort to better understand the nature of kinase inhibition across the kinome, especially as it relates to off-target effects, we screened a well-defined collection of kinase inhibitors using biochemical assays for inhibitory activity against 234 active human kinases and kinase complexes, representing all branches of the kinome tree. For our study we employed 158 small molecules initially identified in the literature as potent and specific inhibitors of kinases important as therapeutic targets and/or signal transduction regulators. Hierarchical clustering of these benchmark kinase inhibitors on the basis of their kinome activity profiles illustrates how they relate to chemical structure similarities and provides new insights into inhibitor specificity and potential applications for probing new targets. Using this broad dataset, we provide a framework for assessing polypharmacology. We not only discover likely off-target inhibitor activities and recommend specific inhibitors for existing targets, but also identify potential new uses for known small molecules.

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Venkatachalam, Prerana, und Varalakshmi Kilingar Nadumane. „Purification and Characterization of a Protease Inhibitor with Anticancer Potential from Bacillus endophyticus JUPR15“. Current Cancer Therapy Reviews 15, Nr. 1 (22.02.2019): 74–82. http://dx.doi.org/10.2174/1573394714666180321150605.

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Introduction:Introduction: Protease Inhibitors (PIs) constitute a group of proteins widely distributed among all organisms and their main function includes their ability to inhibit the proteolytic activity. PIs represent an important role in the regulation of various cellular physiological and biological processes, including cell cycle, cell death, differentiation and immune response.Material and Methods:Hence, in our search for novel anticancer compounds, we isolated microorganisms from various environmental sources and screened them for the production of protease inhibitors. Promising isolates were further checked for their protease inhibitory activity by their ability to inhibit the activity of trypsin and chymotrypsin, which were measured spectrophotometrically.Results:The isolate identified as Bacillus endophyticus JUPR15 was found to be promising with higher inhibitory activity than the other isolates. The inhibitor was purified by cold acetone precipitation and column chromatography and further subjected to characterization studies by performing 12 % SDS-PAGE to determine the molecular weight and gelatin-PAGE assay to confirm its inhibitory activity.Conclusion:The isolate exhibited promising anticancer activity on in-vitro Hela and HepG2 cancer cell lines, showing its application potentials.

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Zhang, Xiaoyin, Yue He, Zhanbo Xiong, Min Li, Ming Li, Nan Zheng, Shengguo Zhao und Jiaqi Wang. „Chelerythrine Chloride: A Potential Rumen Microbial Urease Inhibitor Screened by Targeting UreG“. International Journal of Molecular Sciences 22, Nr. 15 (30.07.2021): 8212. http://dx.doi.org/10.3390/ijms22158212.

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Inhibition of ruminal microbial urease is of particular interest due to its crucial role in regulating urea-N utilization efficiency and nitrogen pollution in the livestock industry. Acetohydroxamic acid (AHA) is currently the only commercially available urease inhibitor, but it has adverse side effects. The urease accessory protein UreG, which facilitates the functional incorporation of the urease nickel metallocentre, has been proposed in developing urease inhibitor through disrupting urease maturation. The objective of this study was to screen natural compounds as potential urease inhibitors by targeting UreG in a predominant ruminal microbial urease. In silico screening and in vitro tests for potential inhibitors were performed using molecular docking and an assay for the GTPase activity of UreG. Chelerythrine chloride was selected as a potential urease inhibitor of UreG with an inhibition concentration IC50 value of 18.13 μM. It exhibited mixed inhibition, with the Ki value being 26.28 μM. We further explored its inhibition mechanism using isothermal titration calorimetry (ITC) and circular dichroism (CD) spectroscopy, and we found that chelerythrine chloride inhibited the binding of nickel to UreG and induced changes in the secondary structure, especially the α-helix and β-sheet of UreG. Chelerythrine chloride formed a pi-anion interaction with the Asp41 residue of UreG, which is an important residue in initiating the conformational changes of UreG. In conclusion, chelerythrine chloride exhibited a potential inhibitory effect on urease, which provided new evidence for strategies to develop novel urease inhibitors targeting UreG to reduce nitrogen excretion from ruminants.

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Sasaki-Tanaka, Reina, Kalyan C. Nagulapalli Venkata, Hiroaki Okamoto, Mitsuhiko Moriyama und Tatsuo Kanda. „Evaluation of Potential Anti-Hepatitis A Virus 3C Protease Inhibitors Using Molecular Docking“. International Journal of Molecular Sciences 23, Nr. 11 (27.05.2022): 6044. http://dx.doi.org/10.3390/ijms23116044.

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Hepatitis A virus (HAV) infection is a major cause of acute hepatitis worldwide and occasionally causes acute liver failure and can lead to death in the absence of liver transplantation. Although HAV vaccination is available, the prevalence of HAV vaccination is not adequate in some countries. Additionally, the improvements in public health reduced our immunity to HAV infection. These situations motivated us to develop potentially new anti-HAV therapeutic options. We carried out the in silico screening of anti-HAV compounds targeting the 3C protease enzyme using the Schrodinger Modeling software from the antiviral library of 25,000 compounds to evaluate anti-HAV 3C protease inhibitors. Additionally, in vitro studies were introduced to examine the inhibitory effects of HAV subgenomic replicon replication and HAV HA11-1299 genotype IIIA replication in hepatoma cell lines using luciferase assays and real-time RT-PCR. In silico studies enabled us to identify five lead candidates with optimal binding interactions in the active site of the target HAV 3C protease using the Schrodinger Glide program. In vitro studies substantiated our hypothesis from in silico findings. One of our lead compounds, Z10325150, showed 47% inhibitory effects on HAV genotype IB subgenomic replicon replication and 36% inhibitory effects on HAV genotype IIIA HA11-1299 replication in human hepatoma cell lines, with no cytotoxic effects at concentrations of 100 μg/mL. The effects of the combination therapy of Z10325150 and RNA-dependent RNA polymerase inhibitor, favipiravir on HAV genotype IB HM175 subgenomic replicon replication and HAV genotype IIIA HA11-1299 replication showed 64% and 48% inhibitory effects of HAV subgenomic replicon and HAV replication, respectively. We identified the HAV 3C protease inhibitor Z10325150 through in silico screening and confirmed the HAV replication inhibitory activity in human hepatocytes. Z10325150 may offer the potential for a useful HAV inhibitor in severe hepatitis A.

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Hayashi, Masayasu, Yoshikane Kikushige, Takuya Harada, Toshihiro Miyamoto, Takahiro Maeda und Koichi Akashi. „Somatic Mutations Potentiating RAS-MAPK Signaling Confer Resistant Potential Against FLT3-Inhibitors to Acute Myelogenous Leukemia“. Blood 134, Supplement_1 (13.11.2019): 910. http://dx.doi.org/10.1182/blood-2019-130694.

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Acute myeloid leukemia (AML) is one of the most common hematologic malignancies derived from a small number of self-renewing leukemic stem cells (LSCs). AML has various genetic abnormalities such as chromosomal aberration, single nucleotide variant and insertion/deletion. In particular, internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) is the most frequently found in ~ 25 % of AML cases, moreover, AML with FLT3-ITD is classified in unfavorable. FLT3 is fundamentally essential for survival of hematopoietic stem cells (HSCs) as well as LSCs, but once ITD is acquired, FLT3-ITD promotes the proliferation of AML by activating downstream enzymes. Various FLT3 inhibitors are now available as effective and promising drugs. On the other hand, the resistance against those inhibitors has been regarded as an emerging problem in clinics. To clarify the molecular machineries how AML cells acquire the resistance against FLT3 inhibitors, we compared the mutation status of paired AML samples consisted of diagnostic and relapsed samples. LSCs, which are quiescent and highly resistant against conventional chemotherapies, are considered to play a central role in recurrence. Since we and other group previously reported that TIM-3 clearly discriminates LSCs from residual normal HSCs, we purified and evaluated the mutations of CD34+CD38-TIM-3+ LSCs or CD34+ immature AML cells. The paired diagnostic and relapsed samples obtained from the identical 5 AML patient treated with Gilteritinib were subjected to whole exome sequencing (WES) analysis. CD3+ T cells were also purified from the diagnostic samples and used as a germ line control to detect somatic mutations acquired in AML cells. Libraries for WES were prepared using Sure Select XT HS and Human All Exon V6 Capture Kit in accordance with manufacturer's instructions. Then we performed WES using NextSeq 500 with 150bp pair-end read. Surprisingly, in all 5 cases examined, AML clones lost FLT3-ITD, whereas clones harboring mutations potentiating RAS-MAPK signaling became dominant at relapse: one case acquired the activated KRAS (Q61H) mutation and the remaining four cases newly acquired the previously-unidentified mutations in RAS-MAPK inhibitory genes. Such mutations in RAS-MAPK-inhibitory genes include DIRAS3 (W173X), RASA1 (E70G), RAP1GAP2 (K18X), RIN2 (S355fs), RASA4 (C655R), RASA4B (E141G), MAP2K7 (T66P) and PTPN7 (T14M). Of note, these genes belong to RAS-MAPK-inhibitory pathways and the encoded proteins are reported to suppress the activity of RAS-MAPK pathways. These RAS-MAPK-inhibitory mutations were exclusively detected in the relapsed AML clones, and contained stop-gain and frameshift mutations. We, therefore, hypothesized that RAS/MAPK activation driven by somatic mutations contributes to the acquisition of resistance against FLT3 inhibitors in LSCs. Consistent with such hypothesis, phosflow analysis revealed that basal ERK phosphorylation was retained or rather increased in the relapse CD34+ AML cells lacking FLT3-ITD, indicating that RAS-MAPK activation was maintained independent of FLT3-ITD. Furthermore, ASP2215 and AC220 inhibited ERK phosphorylation in the diagnostic CD34+ AML cells, whereas both inhibitors failed in the inhibition of ERK activation in the relapsed AML clones in all 3 cases analyzed. Gilteritinib also failed in inhibiting ERK in other relapsed AML cases, however, the combination of ASP2215 and MEK inhibitor efficiently suppressed ERK phosphorylation. All of relapse AML cases exhibited the emergence of AML clones harboring mutations associated with RAS-MAPK pathway genes, and therefore, the clinical sequence for detecting such mutations might be useful to assess the risk of FLT3-inhibitor treatment failure in clinics. Furthermore, our study showed the efficacy of MEK inhibitors to inhibit RAS-MAPK signaling activity even in the relapsed AML cells. Thus, the combination therapy consisted of FLT3-inhibitors and MEK inhibitors might be one of the promising therapeutic strategies to overcome FLT3-inhibitor resistance in AML. In summary, our study revealed that mutations potentiating RAS-MAPK pathway should play a central role in conferring the resistance against FLT3-inhibitors to AML. Disclosures Akashi: Sumitomo Dainippon, Kyowa Kirin: Consultancy; Celgene, Kyowa Kirin, Astellas, Shionogi, Asahi Kasei, Chugai, Bristol-Myers Squibb: Research Funding.

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Son, Yun Gon, Ju Yeon Kim, Jae Yeon Park, Kwang Dong Kim, Ki Hun Park und Jeong Yoon Kim. „Inhibitory Potential of Quercetin Derivatives Isolated from the Aerial Parts of Siegesbeckia pubescens Makino against Bacterial Neuraminidase“. Molecules 28, Nr. 14 (12.07.2023): 5365. http://dx.doi.org/10.3390/molecules28145365.

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This study aimed to isolate bacterial neuraminidase (BNA) inhibitory O-methylated quercetin derivatives from the aerial parts of S. pubescens. All the isolated compounds were identified as O-methylated quercetin (1–4), which were exhibited to be noncompetitive inhibitors against BNA, with IC50 ranging from 14.0 to 84.1 μM. The responsible compounds (1–4) showed a significant correlation between BNA inhibitory effects and the number of O-methyl groups on quercetin; mono (1, IC50 = 14.0 μM) > di (2 and 3, IC50 = 24.3 and 25.8 μM) > tri (4, IC50 = 84.1 μM). In addition, the binding affinities between BNA and inhibitors (1–4) were also examined by fluorescence quenching effect with the related constants (KSV, KA, and n). The most active inhibitor 1 possessed a KSV with 0.0252 × 105 L mol−1. Furthermore, the relative distribution of BNA inhibitory O-methylated quercetins (1–4) in S. pubescens extract was evaluated using LC-Q-TOF/MS analysis.

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Khunluck, Tueanjai, Veerapol Kukongviriyapan, Laddawan Senggunprai, Wutthipong Duangarsong und Auemduan Prawan. „The Inhibition Kinetics and Potential Anti-Migration Activity of NQO1 Inhibitory Coumarins on Cholangiocarcinoma Cells“. Integrative Cancer Therapies 18 (25.12.2018): 153473541882044. http://dx.doi.org/10.1177/1534735418820444.

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Altered expression of a cytosolic flavoenzyme NAD(P)H:quinone oxidoreductase-1 (NQO1) has been seen in many human tumors. Its remarkable overexpression in cholangiocarcinoma (CCA; an aggressive malignancy of the biliary duct system) was associated with poor prognosis and short survival of the patients. Inhibition of NQO1 has been proposed as a potential strategy to improve the efficacy of anticancer drugs in various cancers including CCA. This study investigated novel NQO1 inhibitors and verified the mechanisms of their enzyme inhibition. Among the different chemical classes of natural NQO1 inhibitors are coumarins, flavonoids, and triterpenoids. Coumarins are a group of particularly potent NQO1 inhibitors. The mechanisms and kinetics of enzyme inhibition of coumarin, aesculetin, umbelliferone, and scopoletin using the cell lysates as a source of NQO1 enzyme best fit with an uncompetitive inhibition model. Among the NOQ1 inhibitors tested in KKU-100 CCA cells, scopoletin and umbelliferone had the strongest inhibitory effect on this enzyme, while aesculetin and coumarin barely affected intracellular NQO1. All coumarins were further tested for cytotoxicity and anti-migration activity. At modest cytotoxic doses, scopoletin and umbelliferone greatly inhibited the migration of KKU-100 cells, whereas coumarin and aesculetin barely reduced cell migration. The anti-migration effect of scopoletin was associated with decreased ratio of matrix metalloproteinase 9/tissue inhibitors of metalloproteinases 1 ( MMP9/ TIMP1) mRNA. These findings suggest that natural compounds with potent inhibitory effect on intracellular NQO1 have useful anti-migration effects on CCA cells. In order to prove that the potent NQO1 inhibitor, scopoletin, is clinically useful in the enhancement of CCA treatment, additional in vivo studies to elucidate the mechanism of these effects are needed.

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Kurihara, Hideyuki, und Kazuki Kujira. „Phlorotannins Derived From the Brown Alga Colpomenia bullosa as Tyrosinase Inhibitors“. Natural Product Communications 16, Nr. 7 (Juli 2021): 1934578X2110213. http://dx.doi.org/10.1177/1934578x211021317.

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Tyrosinase catalyzes hydroxylation of L-tyrosine and dehydrogenation of L-DOPA in the melanin biosynthesis pathway. Tyrosinase inhibitors have potential use as cosmetic whitening agents and for preventing seafood deterioration. In this report, tyrosinase inhibitors extracted from brown alga Colpomenia bullosa (Scytosiphonaceae, Scytosiphonales) were investigated. Inhibitory principles were isolated from the extract and identified as phlorotannins, phloroglucinol (1), diphlorethol (2), triphlorethol C (3), which have not been isolated in a free form previously, and fucophlorethol C (4). Compounds 3 and 4 have not been reported previously as tyrosinase inhibitors. Triphlorethol C (3) was the most potent tyrosinase inhibitor among the phlorotannins isolated, whereas isomeric fucophlorethol C (4) displayed the weakest inhibitory activity. The results suggest that molecular structures of phlorotannins strongly affect their tyrosinase inhibitory activity.

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Habash, Maha, Sami Alshakhshir, Shady Awwad und Mahmoud Abu-Samak. „The discovery of potential tumor necrosis factor alpha converting enzyme inhibitors via implementation of K Nearest Neighbor QSAR analysis“. Pharmacia 70, Nr. 2 (12.04.2023): 247–61. http://dx.doi.org/10.3897/pharmacia.70.e96423.

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Tumor necrosis factor-alpha converting enzyme (TACE) is considered as a pro-inflammatory cytokine which catalyzes the formation of TNF-α from membrane bound TNF-α precursor protein. It has important role in various pathological diseases such as inflammation, anorexia, rheumatoid arthritis, cancer and viral replication. Despite the reporting of a variety of TACE inhibitors of diverse chemical scaffolds whether peptide, peptide-like compounds or others, the bioavailability and pharmacokinetic problems are reflected strongly on its clinical effectiveness. In this effort we employed a novel combination of k-nearest neighbor QSAR modeling to select the best critical ligand-TACE contacts capable of elucidation of TACE inhibitory bioactivity among a long list of inhibitors. The recurrence of one valid pharmacophore hypothesis among the successful models emerged the pharmacophore to be used as 3D search queries to screen the National Cancer Institute’s structural database for new TACE inhibitors. Eight potent TACE inhibitors were discovered with inhibition percentage exceeding 50% at 100 μM inhibitor concentration.

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Kopecký, Jindřich. „New potential checkpoint inhibitors in cancer therapy“. Onkologie 16, Nr. 3 (16.05.2022): 115–17. http://dx.doi.org/10.36290/xon.2022.022.

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Jeng, Arco Y., Paul Mulder, Aij-Lie Kwan und Bruno Battistini. „Nonpeptidic endothelin-converting enzyme inhibitors and their potential therapeutic applications“. Canadian Journal of Physiology and Pharmacology 80, Nr. 5 (01.05.2002): 440–49. http://dx.doi.org/10.1139/y02-025.

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Endothelins (ETs) are potent vasoconstrictors, promitogens, and inflammatory mediators. They have been implicated in the pathogenesis of various cardiovascular, renal, pulmonary, and central nervous system diseases. Since the final step of the biosynthesis of ETs is catalyzed by a family of endothelin-converting enzymes (ECEs), inhibitors of these enzymes may represent novel therapeutic agents. Currently, seven isoforms of these metalloproteases have been identified; they all share a significant amino acid sequence identity with neutral endopeptidase 24.11 (NEP), another metalloprotease. Therefore, it is not surprising that the majority of ECE inhibitors also possess potent NEP inhibitory activity. To date, three classes of ECE inhibitors have been synthesized: dual ECE/NEP inhibitors, triple ECE/NEP/ACE inhibitors, and selective ECE inhibitors. Potential clinical applications of these compounds in hypertension, chronic heart failure, restenosis, renal failure, and cerebral vasospasm deduced from studies with relevant animal models are reviewed.Key words: endothelin-converting enzyme, ECE, inhibitors, phosphoramidon, CGS 26303, CGS 35066, FR 901533, SCH 54470, metalloprotease.

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Han, Yoo Kyong, Ji Sun Lee, Seo Young Yang, Ki Yong Lee und Young Ho Kim. „In Vitro and In Silico Studies of Soluble Epoxide Hydrolase Inhibitors from the Roots of Lycopus lucidus“. Plants 10, Nr. 2 (13.02.2021): 356. http://dx.doi.org/10.3390/plants10020356.

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Soluble epoxide hydrolase (sEH) is an enzyme that is considered a potential therapeutic target in human cardiovascular disease. Triterpenes (1–4) and phenylpropanoids (5–10) were isolated from Lycopus lucidus to obtain sEH inhibitors through various chromatographic purificationtechniques. The isolated compounds were evaluated for their inhibitory activity against sEH, and methyl rosmarinate (7), martynoside (8), dimethyl lithospermate (9) and 9″ methyl lithospermate (10) showed remarkable inhibitory activity, with the IC50 values ranging from 10.6 ± 3.2 to 35.7 ± 2.1 µM. Kinetic analysis of these compounds revealed that 7, 9 and 10 were competitive inhibitors bound to the active site, and 8 was the preferred mixed type inhibitor for allosteric sites. Additionally, molecular modeling has identified interacting catalytic residues and bindings between sEH and inhibitors. The results suggest that these compounds are potential candidates that can be used for further development in the prevention and treatment for cardiovascular risk.

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Mia, Md Abdur Rashid, Qamar Uddin Ahmed, Sahena Ferdosh, Abul Bashar Mohammed Helaluddin, Md Shihabul Awal, Murni Nazira Sarian, Md Zaidul Islam Sarker und Zainul Amiruddin Zakaria. „In Vitro, In Silico and Network Pharmacology Mechanistic Approach to Investigate the α-Glucosidase Inhibitors Identified by Q-ToF-LCMS from Phaleria macrocarpa Fruit Subcritical CO2 Extract“. Metabolites 12, Nr. 12 (15.12.2022): 1267. http://dx.doi.org/10.3390/metabo12121267.

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The fruit of Phaleria macrocarpa have been traditionally used as an antidiabetic remedy in Malaysia and neighbouring countries. Despite its potential for diabetes treatment, no scientific study has ever been conducted to predict the inhibitor interaction of the protein α-glucosidase identified in an extract prepared with a non-conventional extraction technique. Hence, the major aim of this research was to evaluate the in vitro antioxidant, the α-glucosidase inhibitors, and the molecular dynamic simulations of the α-glucosidase inhibitors identified by Quadrupole Time-of-Flight Liquid Chromatography Mass Spectrometry (Q-ToF-LCMS) analysis. Initially, dry fruit were processed using non-conventional and conventional extraction methods to obtain subcritical carbon dioxide extracts (SCE-1 and SCE-2) and heating under reflux extract (HRE), respectively. Subsequently, all extracts were evaluated for their in vitro antioxidative and α-glucosidase inhibitory potentials. Subsequently, the most bioactive extract (SCE-2) was subjected to Q-ToF-LCMS analysis to confirm the presence of α-glucosidase inhibitors, which were then analysed through molecular dynamic simulations and network pharmacology approaches to confirm their possible mechanism of action. The highest inhibitory effects of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and α-glucosidase on SCE-2 was found as 75.36 ± 0.82% and 81.79 ± 0.82%, respectively, compared to the SCE-1 and HRE samples. The Q-ToF-LCMS analysis tentatively identified 14 potent α-glucosidase inhibitors. Finally, five identified compounds, viz., lupenone, swertianolin, m-coumaric acid, pantothenic acid, and 8-C-glucopyranosyleriodictylol displayed significant stability, compactness, stronger protein-ligand interaction up to 100 ns further confirming their potential as α-glucosidase inhibitors. Consequently, it was concluded that the SCE-2 possesses a strong α-glucosidase inhibitory effect due to the presence of these compounds. The findings of this study might prove useful to develop these compounds as alternative safe α-glucosidase inhibitors to manage diabetes more effectively.

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Sattler, Martin, Isa Mambetsariev, Jeremy Fricke, Tingting Tan, Sariah Liu, Nagarajan Vaidehi, Evan Pisick et al. „A Closer Look at EGFR Inhibitor Resistance in Non-Small Cell Lung Cancer through the Lens of Precision Medicine“. Journal of Clinical Medicine 12, Nr. 5 (01.03.2023): 1936. http://dx.doi.org/10.3390/jcm12051936.

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The development of EGFR small-molecule inhibitors has provided significant benefit for the affected patient population. Unfortunately, current inhibitors are no curative therapy, and their development has been driven by on-target mutations that interfere with binding and thus inhibitory activity. Genomic studies have revealed that, in addition to these on-target mutations, there are also multiple off-target mechanisms of EGFR inhibitor resistance and novel therapeutics that can overcome these challenges are sought. Resistance to competitive 1st-generation and covalent 2nd- and 3rd-generation EGFR inhibitors is overall more complex than initially thought, and novel 4th-generation allosteric inhibitors are expected to suffer from a similar fate. Additional nongenetic mechanisms of resistance are significant and can include up to 50% of the escape pathways. These potential targets have gained recent interest and are usually not part of cancer panels that look for alterations in resistant patient specimen. We discuss the duality between genetic and nongenetic EGFR inhibitor drug resistance and summarize current team medicine approaches, wherein clinical developments, hand in hand with drug development research, drive potential opportunities for combination therapy.

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Kondža, Martin, Mirza Bojić, Ivona Tomić, Željan Maleš, Valentina Rezić und Ivan Ćavar. „Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids“. Molecules 26, Nr. 10 (19.05.2021): 3018. http://dx.doi.org/10.3390/molecules26103018.

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Acacetin, apigenin, chrysin, and pinocembrin are flavonoid aglycones found in foods such as parsley, honey, celery, and chamomile tea. Flavonoids can act as substrates and inhibitors of the CYP3A4 enzyme, a heme containing enzyme responsible for the metabolism of one third of drugs on the market. The aim of this study was to investigate the inhibitory effect of selected flavonoids on the CYP3A4 enzyme, the kinetics of inhibition, the possible covalent binding of the inhibitor to the enzyme, and whether flavonoids can act as pseudo-irreversible inhibitors. For the determination of inhibition kinetics, nifedipine oxidation was used as a marker reaction. A hemochromopyridine test was used to assess the possible covalent binding to the heme, and incubation with dialysis was used in order to assess the reversibility of the inhibition. All the tested flavonoids inhibited the CYP3A4 enzyme activity. Chrysin was the most potent inhibitor: IC50 = 2.5 ± 0.6 µM, Ki = 2.4 ± 1.0 µM, kinact = 0.07 ± 0.01 min−1, kinact/Ki = 0.03 min−1 µM−1. Chrysin caused the highest reduction of heme (94.5 ± 0.5% residual concentration). None of the tested flavonoids showed pseudo-irreversible inhibition. Although the inactivation of the CYP3A4 enzyme is caused by interaction with heme, inhibitor-heme adducts could not be trapped. These results indicate that flavonoids have the potential to inhibit the CYP3A4 enzyme and interact with other drugs and medications. However, possible food–drug interactions have to be assessed clinically.

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Colland, Frédéric. „The therapeutic potential of deubiquitinating enzyme inhibitors“. Biochemical Society Transactions 38, Nr. 1 (19.01.2010): 137–43. http://dx.doi.org/10.1042/bst0380137.

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Proteases play a key role in various pathological processes and several protease inhibitors are already available for treatment. DUBs (deubiquitinating enzymes) constitute one of the largest classes of human proteases and are key effectors of the ubiquitin–proteasome system. This pathway regulating cellular protein turnover has been implicated in the pathogenesis of many human diseases, including neurodegenerative disorders, viral diseases and cancer. The therapeutic efficacy of the proteasome inhibitor Velcade® (bortezomib) for treating multiple myeloma and mantle cell lymphoma establishes this system as a valid target for cancer treatment. A promising alternative to targeting the proteasome itself would be to target the upstream, ubiquitin conjugation/deconjugation system, to generate more specific, less toxic anticancer agents. Advances in small molecule-based inhibitors specifically targeting DUBs are presented in this review.

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Pertwee, Roger G. „Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications“. Proceedings of the Nutrition Society 73, Nr. 1 (18.10.2013): 96–105. http://dx.doi.org/10.1017/s0029665113003649.

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The endocannabinoid system consists of cannabinoid CB1 and CB2 receptors, of endogenous agonists for these receptors known as ‘endocannabinoids’, and of processes responsible for endocannabinoid biosynthesis, cellular uptake and metabolism. There is strong evidence first, that this system up-regulates in certain disorders as indicated by an increased release of endocannabinoids onto their receptors and/or by increases in the expression levels or coupling efficiency of these receptors, and second, that this up-regulation often appears to reduce or abolish unwanted effects of these disorders or to slow their progression. This discovery has raised the possibility of developing a medicine that enhances up-regulation of the endocannabinoid system associated with these disorders by inhibiting the cellular uptake or intracellular metabolism of an endocannabinoid following its ‘autoprotective’ endogenous release. For inhibition of endocannabinoid metabolism, research has focused particularly on two highly investigated endocannabinoids, anandamide and 2-arachidonoyl glycerol, and hence on inhibitors of the main anandamide-metabolising enzyme, fatty acid amide hydrolase (FAAH), and of the main 2-arachidonoyl glycerol-metabolising enzyme, monoacylglycerol (MAG) lipase. The resulting data have provided strong preclinical evidence that selective FAAH and MAG lipase inhibitors would ameliorate the unwanted effects of several disorders, when administered alone or with a cyclooxygenase inhibitor, and that the benefit-to-risk ratio of a FAAH inhibitor would exceed that of a MAG lipase inhibitor or dual inhibitor of FAAH and MAG lipase. Promising preclinical data have also been obtained with inhibitors of endocannabinoid cellular uptake. There is now an urgent need for clinical research with these enzyme and uptake inhibitors.

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Sanni, Omotayo, Samuel Ayodele Iwarere und Michael Olawale Daramola. „Investigation of Eggshell Agro-Industrial Waste as a Potential Corrosion Inhibitor for Mild Steel in Oil and Gas Industry“. Sustainability 15, Nr. 7 (03.04.2023): 6155. http://dx.doi.org/10.3390/su15076155.

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Corrosion inhibitors are generally used in reducing metallic corrosive effects. Nevertheless, most inhibitory compounds have harmful effects on the environment, as well as being expensive and toxic. Therefore, there is growing awareness of the need to replace petroleum inhibitors with eco-friendly inhibitors. Eggshell agro-industrial waste (ESAW) is a compound with high inhibitive activity and its utilization is desirable to minimize the quantity of agricultural waste generated. Hence, this study aims to demonstrate the inhibition efficiency of eggshell extract, a waste compound, on mild steel (material frequently utilized in the oil and gas sector) in one molar hydrochloric acid solution accessed via weight loss and electrochemical methods. Potentiodynamic polarization results shows that the current densities of mild steel corrosion significantly decreased using eggshell agro-industrial waste. Similarly, electrochemical impedance spectroscopy results suggest that eggshell agro-industrial waste enhances the mild steel polarization resistance significantly. The inhibitor performance increases with increasing eggshell agro-industrial waste concentration, with optimum efficiency of 97.17%. The inhibition was due to the adsorption and adhesion of the eggshell agro-industrial waste constituents on the surface of the mild steel; the adsorption obeys the Langmuir adsorption isotherm model. Compared with various reported corrosion inhibitors in the literature, eggshell agro-industrial waste is very effective. Therefore, eggshell agro-industrial waste can be recommended as a potential inhibitor in the oil and gas sector.

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Basak, Debasish, David Gamez und Subrata Deb. „SGLT2 Inhibitors as Potential Anticancer Agents“. Biomedicines 11, Nr. 7 (30.06.2023): 1867. http://dx.doi.org/10.3390/biomedicines11071867.

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Sodium-glucose cotransporter 2 (SGLT2) serves as a critical glucose transporter that has been reported to be overexpressed in cancer models, followed by increased glucose uptake in both mice and humans. Inhibition of its expression can robustly thwart tumor development in vitro and in vivo. SGLT2 inhibitors are a comparatively new class of antidiabetic drugs that have demonstrated anticancer effects in several malignancies, including breast, liver, pancreatic, thyroid, prostate, and lung cancers. This review aims to assess the extent of SGLT involvement in different cancer cell lines and discuss the pharmacology, mechanisms of action, and potential applications of SGLT2 inhibitors to reduce tumorigenesis and its progression. Although these agents display a common mechanism of action, they exhibit distinct affinity towards the SGLT type 2 transporter compared to the SGLT type 1 transporter and varying extents of bioavailability and half-lives. While suppression of glucose uptake has been attributed to their primary mode of antidiabetic action, SGLT2 inhibitors have demonstrated several mechanistic ways to combat cancer, including mitochondrial membrane instability, suppression of β-catenin, and PI3K-Akt pathways, increase in cell cycle arrest and apoptosis, and downregulation of oxidative phosphorylation. Growing evidence and ongoing clinical trials suggest a potential benefit of combination therapy using an SGLT2 inhibitor with the standard chemotherapeutic regimen. Nevertheless, further experimental and clinical evidence is required to characterize the expression and role of SGLTs in different cancer types, the activity of different SGLT subtypes, and their role in tumor development and progression.

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Kholilah, Tsaniyah, Nashi Widodo und Nia Kurniawan. „in silico Study Reveals Potential Docking Sites of δ 2-isoxazolines derivates for Inhibiting Russell’s Viper PLA2 Toxin“. Journal of Tropical Life Science 11, Nr. 1 (03.02.2021): 45–51. http://dx.doi.org/10.11594/jtls.11.01.06.

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Snake venom phospholipase A2s (svPLA2s) has been known as the most abundant component and predominant cause of Russell’s viper envenomation. Limitation to serum therapy and considerable pharmacological interest led the researcher to synthesized multi-toxic PLA2 inhibitors, δ2-isoxazolines derivate. Although δ2- isoxazolines derivate already proved inhibitor activity in Group II svPLA2 with known IC50, their mechanism of action remains unveiled. Our recent study investigated their inhibitory activity via molecular docking. The virtual screening revealed that the ligand with diverse structures tied to the relatively same active site region. The result sheds light on the significance of His48 and Asp49 as part of the pro-inflammatory eliciting region. ADME analysis was also performed to filter and identify the best potential inhibitor acceptable for human use. This moiety leads to finding a better therapeutic strategy of svPLA2 inhibitors both as an alternative to serum anti-venom treatment.

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ALIAS, ZAZALI, und NORA ASYIKIN RAMLI. „PURIFICATION AND PARTIAL CHARACTERISATION OF A PROTEASE INHIBITOR FROM Mimosa diplotricha“. Malaysian Applied Biology 51, Nr. 4 (31.10.2022): 169–75. http://dx.doi.org/10.55230/mabjournal.v51i4.26.

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Search for inhibitors to insect proteases is one of many strategies to control pests. Previous work has demonstrated successful purification of effective inhibitors from plant origin. Thus, the current study attempted to purify protease inhibitors from locally available medicinal plants. The study demonstrated that the ethanolic extracts of Mimosa diplotricha leaves caused a significant 80% reduction in bovine trypsin activity. The inhibitory property of the proteinaceous nature of the extract was reconfirmed through qualitative analysis using the detection of trypsin inhibitors on the SDS-PAGE technique. The ammonium precipitated trypsin inhibitor was purified using Hi-Trap G25 and resolved into a single band with a molecular weight of approximately 20.8 kDa. By using the Dixon plot the competitive inhibitor has a Ki value of 2.16 × 10-4 mM. The purified protein inhibited the protease extract of Chrysomya megacephala at IC50 of 28 μg/mL. The results highlighted the presence of trypsin inhibitor in Mimosa diplotricha and its potential as a pest control agent.

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Han, Seungmin, Kwang Suk Lim, Brody J. Blackburn, Jina Yun, Charles W. Putnam, David A. Bull und Young-Wook Won. „The Potential of Topoisomerase Inhibitor-Based Antibody–Drug Conjugates“. Pharmaceutics 14, Nr. 8 (16.08.2022): 1707. http://dx.doi.org/10.3390/pharmaceutics14081707.

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DNA topoisomerases are essential enzymes that stabilize DNA supercoiling and resolve entanglements. Topoisomerase inhibitors have been widely used as anti-cancer drugs for the past 20 years. Due to their selectivity as topoisomerase I (TOP1) inhibitors that trap TOP1 cleavage complexes, camptothecin and its derivatives are promising anti-cancer drugs. To increase accumulation of TOP1 inhibitors in cancer cells through the targeting of tumors, TOP1 inhibitor antibody–drug conjugates (TOP1-ADC) have been developed and marketed. Some TOP1-ADCs have shown enhanced therapeutic efficacy compared to prototypical anti-cancer ADCs, such as T-DM1. Here, we review various types of camptothecin-based TOP1 inhibitors and recent developments in TOP1-ADCs. We then propose key points for the design and construction of TOP1-ADCs. Finally, we discuss promising combinatorial strategies, including newly developed approaches to maximizing the therapeutic potential of TOP1-ADCs.

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Zhang, Yi-Lin, Yong Yan, Xue-Jun Wang und Ke-Wu Yang. „Synthesis and Bioactivity of Thiazolethioacetamides as Potential Metallo-β-Lactamase Inhibitors“. Antibiotics 9, Nr. 3 (26.02.2020): 99. http://dx.doi.org/10.3390/antibiotics9030099.

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Metallo-β-lactamase (MβLs) mediated antibiotic resistance seriously threatens the treatment of bacterial diseases. Recently, we found that thioacetamides can be a potential MβL inhibitor skeleton. In order to improve the information of the skeleton, twelve new thiazolethioacetamides were designed by modifying the aromatic substituent. Biological activity assays identify the thiazolethioacetamides can inhibit ImiS with IC50 values of 0.17 to 0.70 μM. For two of them, the IC50 values against VIM-2 were 2.2 and 19.2 μM, which is lower than in our previous report. Eight of the thiazolethioacetamides are able to restore antibacterial activity of cefazolin against E.coli-ImiS by 2–4 fold. An analysis of the structure–activity relation and molecule docking show that the style and position of electron withdrawing groups in aromatic substituents play a crucial role in the inhibitory activity of thiazolethioacetamides. These results indicate that thiazolethioacetamides can serve as a potential skeleton of MβL inhibitors.

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Chu, Ming-Jie, Wei Wang, Zi-Li Ren, Hao Liu, Xiang Cheng, Kai Mo, Li Wang, Feng Tang und Xian-Hai Lv. „Discovery of Novel Triazole-Containing Pyrazole Ester Derivatives as Potential Antibacterial Agents“. Molecules 24, Nr. 7 (03.04.2019): 1311. http://dx.doi.org/10.3390/molecules24071311.

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To develop new antibacterial agents, a series of novel triazole-containing pyrazole ester derivatives were designed and synthesized and their biological activities were evaluated as potential topoisomerase II inhibitors. Compound 4d exhibited the most potent antibacterial activity with Minimum inhibitory concentration (MIC) alues of 4 µg/mL, 2 µg/mL, 4 µg/mL, and 0.5 µg/mL against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Salmonella gallinarum, respectively. The in vivo enzyme inhibition assay 4d displayed the most potent topoisomerase II (IC50 = 13.5 µg/mL) and topoisomerase IV (IC50 = 24.2 µg/mL) inhibitory activity. Molecular docking was performed to position compound 4d into the topoisomerase II active site to determine the probable binding conformation. In summary, compound 4d may serve as potential topoisomerase II inhibitor.

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R. Somani, Rakesh, und Mayuri H. Patel. „Telomerase Inhibitors: Potential Anticancer Agents“. Mini-Reviews in Organic Chemistry 13, Nr. 1 (04.03.2016): 49–61. http://dx.doi.org/10.2174/1570193x13666160225000624.

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Elias, Daniel, und Henrik J. Ditzel. „The potential of Src inhibitors“. Aging 7, Nr. 10 (02.10.2015): 734–35. http://dx.doi.org/10.18632/aging.100821.

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Lazarevic-Pasti, Tamara, Andreja Leskovac und Vesna Vasic. „Myeloperoxidase Inhibitors as Potential Drugs“. Current Drug Metabolism 16, Nr. 3 (12.08.2015): 168–90. http://dx.doi.org/10.2174/138920021603150812120640.

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Derler, Isabella, Reinhard Fritsch, Rainer Schindl und Christoph Romanin. „CRAC inhibitors: identification and potential“. Expert Opinion on Drug Discovery 3, Nr. 7 (23.06.2008): 787–800. http://dx.doi.org/10.1517/17460441.3.7.787.

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Verstovsek, Srdan. „Therapeutic Potential of JAK2 Inhibitors“. Journal of OncoPathology 1, Nr. 1 (01.04.2013): 76–79. http://dx.doi.org/10.13032/tjop.2052-5931.100024.

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Mathe, Christophe, und Vasu Nair. „Potential Inhibitors of HIV Integrase“. Nucleosides and Nucleotides 18, Nr. 4-5 (April 1999): 681–82. http://dx.doi.org/10.1080/15257779908041539.

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LOBL, T. J., H. E. RENIS, R. M. EPAND, L. L. MAGGIORA und M. W. WATHEN. „Peptides as potential virus inhibitors“. International Journal of Peptide and Protein Research 32, Nr. 5 (12.01.2009): 326–30. http://dx.doi.org/10.1111/j.1399-3011.1988.tb01267.x.

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Perry, Martin J., und Gerald A. Higgs. „Chemotherapeutic potential of phosphodiesterase inhibitors“. Current Opinion in Chemical Biology 2, Nr. 4 (Januar 1998): 472–81. http://dx.doi.org/10.1016/s1367-5931(98)80123-3.

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Bedaiwy, Mohamed A., Noha A. Mousa und Robert F. Casper. „Aromatase Inhibitors: Potential Reproductive Implications“. Journal of Minimally Invasive Gynecology 16, Nr. 5 (September 2009): 533–39. http://dx.doi.org/10.1016/j.jmig.2009.05.009.

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Lavin, Martin F., und Abrey J. Yeo. „Clinical potential of ATM inhibitors“. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 821 (Mai 2020): 111695. http://dx.doi.org/10.1016/j.mrfmmm.2020.111695.

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