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Статті в журналах з теми "Small inhibitory compounds":
1
Alvarez-Gonzalez, Juan Antonio, Robert Maul, Rahul M. Kohli, and Patricia J. Gearhart. "Small molecule inhibitors of Activation-Induced Deaminase." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 48.18. http://dx.doi.org/10.4049/jimmunol.200.supp.48.18.
Анотація:
Abstract Activation-Induced Deaminase (AID) is a cytosine deaminase that converts cytosine into uracil in DNA, which initiates a cascade of mutagenic DNA repair to introduce point mutations and double-strand breaks. Specific targeting of AID to the immunoglobulin heavy chain locus promotes somatic hypermutation in antibody variable genes for affinity maturation, and breaks in switch regions for class switch recombination (CSR). However, mis-targeting of AID to other loci could initiate tumor development and lead to greater drug resistance among cancer cells when continually expressed. To identify a small molecule inhibitor of AID, we screened ~400,000 compounds in conjunction with the NCATS core facility at NIH. Using FRET based analysis of cytosine deamination, we identified 150 potential inhibitors of AID catalytic activity. To confirm biological function, we examined their effects on CSR in an in vitro murine B-cell activation assay using CH12 cells, wherein 30 were confirmed inhibitor candidates. We then selected the top seven molecules to proceed with further characterization in wild type primary splenocytes, and found two near-identical compounds that had inhibitory activity. From these structures, we tested commercially available analogues and identified two molecules with inhibitory efficacy in the nanomolar range. Using these approaches, we hope to identify a small molecule with great efficacy and low toxicity for use as a molecular probe to further characterize AID’s intricacies, or even as a therapeutic agent.
2
Yan, Hua, Tomoko Chiba Mizutani, Nobuhiko Nomura, Tadakazu Takakura, Yoshihiro Kitamura, Hideka Miura, Masako Nishizawa, Masashi Tatsumi, Naoki Yamamoto, and Wataru Sugiura. "A Novel Small Molecular Weight Compound with a Carbazole Structure That Demonstrates Potent Human Immunodeficiency Virus Type-1 Integrase Inhibitory Activity." Antiviral Chemistry and Chemotherapy 16, no. 6 (December 2005): 363–73. http://dx.doi.org/10.1177/095632020501600603.
Анотація:
The integration of reverse transcribed proviral DNA into a host genome is an essential event in the human immunodeficiency virus type 1 (HIV-1) replication life cycle. Therefore, the viral enzyme integrase (IN), which plays a crucial role in the integration event, has been an attractive target of anti-retroviral drugs. Several IN inhibitory compounds have been reported previously, yet none has been successful in clinical use. To find a new, more successful IN inhibitor, we screened a diverse library of 12000 small molecular weight compounds randomly by in vitro strand-transfer assay. We identified a series of substituted carbazoles that exhibit strand-transfer inhibitory activity at low micromolar concentrations. Of these, the most potent compound exhibited an IC50 of 5.00 ±3.31 μM (CA-0). To analyse the structural determinants of strand-transfer inhibitory activity of the carbazole derivatives, we selected 23 such derivatives from our compound library and performed further analyses. Of these 23 compounds, six showed strong strand-transfer inhibition. The inhibition kinetics analyses and ethidium bromide displacement assays indicated that the carbazole derivatives are competitive inhibitors and not intercalators. An HeLa4.5/LTR-nEGFP cell line was employed to evaluate in vitro virus replication inhibition of the carbazole derivatives, and IC50 levels ranged from 0.48–1.52 μM. Thus, it is possible that carbazole derivatives, which possess structures different from previously-reported IN inhibitors, may become novel lead compounds in the development of IN inhibitors.
3
Asai, Takashi, Tsutomu Takeuchi, Jeff Diffenderfer, and L. David Sibley. "Identification of Small-Molecule Inhibitors of Nucleoside Triphosphate Hydrolase in Toxoplasma gondii." Antimicrobial Agents and Chemotherapy 46, no. 8 (August 2002): 2393–99. http://dx.doi.org/10.1128/aac.46.8.2393-2399.2002.
Анотація:
ABSTRACT Approximately 150,000 small-molecule compounds were tested by a robotic screening assay for their ability to inhibit nucleoside triphosphate hydrolase (NTPase), a novel enzyme of the tachyzoite form of Toxoplasma gondii. Five unrelated species of compounds were found to inhibit the activities of both NTPase isoforms (NTPase isoform I [NTPase-I] and NTPase-II). The 50% inhibitory concentrations (IC50s) ranged from 0.1 to 20 μM, and in general, the IC50s were similar for both NTPase isoforms. However, the activity of NTPase-I was 20 times more sensitive than the activity of NTPase-II to one of the inhibitors: 9-hydroxy-10-(pentachlorophenoxy)stearic acid. The five compounds identified also prevented tachyzoite replication in vitro, with IC50s ranging from ∼7 to ≥50 μM. The most effective of these initial compounds, 2-phenylthio-indole, was used to identify six additional, structurally related compounds, which were tested for their inhibitory effects on enzyme activities and tachyzoite replication. Surprisingly, these compounds were competitive inhibitors of NTPase-I but noncompetitive inhibitors of NTPase-II. Modifications to the indole and phenol rings resulted in alterations of activity, thus providing insight into the structural features that are important for inhibition of T. gondii NTPases.
4
Patkar, Chinmay G., Martha Larsen, Michael Owston, Janet L. Smith, and Richard J. Kuhn. "Identification of Inhibitors of Yellow Fever Virus Replication Using a Replicon-Based High-Throughput Assay." Antimicrobial Agents and Chemotherapy 53, no. 10 (August 3, 2009): 4103–14. http://dx.doi.org/10.1128/aac.00074-09.
Анотація:
ABSTRACT Flaviviruses cause severe disease in humans and are a public health priority worldwide. However, no effective therapies or drugs are commercially available yet. Several flavivirus replicon-based assays amenable to high-throughput screening of inhibitors have been reported recently. We developed and performed a replicon-based high-throughput assay for screening small-molecule inhibitors of yellow fever virus (YFV) replication. This assay utilized packaged pseudoinfectious particles containing a YFV replicon that expresses Renilla luciferase in a replication-dependent manner. Several small-molecule compounds with inhibitory activity at micromolar concentrations were identified in the high-throughput screen. These compounds were subsequently tested for their inhibitory activities against YFV replication and propagation in low-throughput assays. Furthermore, YFV mutants that escaped inhibition by two of the compounds were isolated, and in both cases, the mutations were mapped to the NS4B coding region, suggesting a novel inhibitory target for these compounds. This study opens up new avenues for pursuing the nonenzymatic nonstructural proteins as targets for antivirals against YFV and other flaviviruses.
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Han, Chun, Jiahong Ren, Feng Su, Xiaoqin Hu, Mengyao Li, Zhijun Wang, and Lintao Wu. "Hybrids of Quinoline and Anilinopyrimidine: Novel EGFRT790M Inhibitors with Antiproliferative Activity against Non-Small Cell Lung Cancer Cell Lines." Anti-Cancer Agents in Medicinal Chemistry 20, no. 6 (June 14, 2020): 724–33. http://dx.doi.org/10.2174/1871520620666200302113206.
Анотація:
Background: The third-generation irreversible Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) inhibit the T790M mutation while sparing EGFRWT. However, the C797S point mutation confers resistance to existing irreversible EGFRT790M inhibitors. Objective: Novel EGFRT790M inhibitors were designed through hybridization of quinoline and anilinopyrimidine, and biologically evaluated their antiproliferative activity against Non-Small Cell Lung Cancer (NSCLC) cell lines. Methods: The target compounds 11a-h were synthesized and structurally characterized with 1H, 13C Nuclear Magnetic Resonance (NMR) spectroscopy and High-Resolution Mass Spectrometry (HRMS). Their inhibitory effects on tumor cell proliferation and EGFR kinase were biologically evaluated. Additionally, molecular docking studies were also performed on the representative typical EGFRT790M inhibitor. Results: Most of the evaluated compounds displayed moderate antiproliferative activity on H1975 cells with EGFRL858R/T790M. However, compound 11a (IC50 = 2.235 ± 0.565μM) showed stronger inhibition than gefitinib (IC50 = 8.830 ± 0.495μM) in concentration- and time-dependent manner. Moreover, compound 11a exhibited weaker inhibitory activities on cells with EGFRWT. Specifically, compound 11a strongly suppressed EGFRL858R/T790M (IC50 = 0.515 ± 0.011μM) relative to EGFRWT (IC50 = 0.913 ± 0.068μM). Furthermore, molecular docking studies demonstrated its strong binding contacts with the EGFRT790M enzyme through hydrogen bonds and other non-bonded interactions. Conclusion: Taken together, these results indicate that the hybrid of quinoline and anilinopyrimidine 11a, could be a potential inhibitor of EGFRT790M in NSCLC, which warrants further in-depth studies.
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Abramić, Marija, and Dejan Agić. "Survey of Dipeptidyl Peptidase III Inhibitors: From Small Molecules of Microbial or Synthetic Origin to Aprotinin." Molecules 27, no. 9 (May 7, 2022): 3006. http://dx.doi.org/10.3390/molecules27093006.
Анотація:
Dipeptidyl peptidase III (DPP III) was originally thought to be a housekeeping enzyme that contributes to intracellular peptide catabolism. More specific roles for this cytosolic metallopeptidase, in the renin-angiotensin system and oxidative stress regulation, were confirmed, or recognized, only recently. To prove indicated (patho)physiological functions of DPP III in cancer progression, cataract formation and endogenous pain modulation, or to reveal new ones, selective and potent inhibitors are needed. This review encompasses natural and synthetic compounds with experimentally proven inhibitory activity toward mammalian DPP III. Except for the polypeptide aprotinin, all others are small molecules and include flavonoids, coumarin and benzimidazole derivatives. Presented are current strategies for the discovery or development of DPP III inhibitors, and mechanisms of inhibitory actions. The most potent inhibitors yet reported (propioxatin A and B, Tyr-Phe- and Phe-Phe-NHOH, and JMV-390) are active in low nanomolar range and contain hydroxamic acid moiety. High inhibitory potential possesses oligopeptides from the hemorphin group, valorphin and tynorphin, which are poor substrates of DPP III. The crystal structure of human DPP III-tynorphin complex enabled the design of the transition-state peptidomimetics inhibitors, effective in low micromolar concentrations. A new direction in the field is the development of fluorescent inhibitor for monitoring DPP III activity.
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Noueiry, Amine O., Paul D. Olivo, Urszula Slomczynska, Yi Zhou, Ben Buscher, Brian Geiss, Michael Engle, et al. "Identification of Novel Small-Molecule Inhibitors of West Nile Virus Infection." Journal of Virology 81, no. 21 (August 22, 2007): 11992–2004. http://dx.doi.org/10.1128/jvi.01358-07.
Анотація:
ABSTRACT West Nile virus (WNV) has spread throughout the United States and Canada and now annually causes a clinical spectrum of human disease ranging from a self-limiting acute febrile illness to acute flaccid paralysis and lethal encephalitis. No therapy or vaccine is currently approved for use in humans. Using high-throughput screening assays that included a luciferase expressing WNV subgenomic replicon and an NS1 capture enzyme-linked immunosorbent assay, we evaluated a chemical library of over 80,000 compounds for their capacity to inhibit WNV replication. We identified 10 compounds with strong inhibitory activity against genetically diverse WNV and Kunjin virus isolates. Many of the inhibitory compounds belonged to a chemical family of secondary sulfonamides and have not been described previously to inhibit WNV or other related or unrelated viruses. Several of these compounds inhibited WNV infection in the submicromolar range, had selectivity indices of greater than 10, and inhibited replication of other flaviviruses, including dengue and yellow fever viruses. One of the most promising compounds, AP30451, specifically blocked translation of a yellow fever virus replicon but not a Sindbis virus replicon or an internal ribosome entry site containing mRNA. Overall, these compounds comprise a novel class of promising inhibitors for therapy against WNV and other flavivirus infections in humans.
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Lefas, Georgia, and George Chaconas. "High-Throughput Screening Identifies Three Inhibitor Classes of the Telomere Resolvase from the Lyme Disease Spirochete." Antimicrobial Agents and Chemotherapy 53, no. 10 (July 13, 2009): 4441–49. http://dx.doi.org/10.1128/aac.00529-09.
Анотація:
ABSTRACT Lyme disease, the most common vector-borne zoonosis in North America, is caused by the spirochetal pathogen Borrelia burgdorferi. The telomere resolvase encoded by this organism (ResT) promotes the formation of covalently closed hairpin ends on the linear DNA molecules of B. burgdorferi through a two-step transesterification. ResT is essential for survival and is therefore an attractive target for the development of highly specific antiborrelial drugs. To identify ResT inhibitors, a novel fluorescence-based high-throughput assay was developed and used to screen a library of 27,520 small-molecule drug-like compounds. Six confirmed inhibitors of ResT, with 50% inhibitory concentrations between 2 and 10 μM, were identified. The inhibitors were characterized further and were grouped into three distinct classes based on their inhibitory features. The high-throughput screening assay developed in this paper, along with the six inhibitory compounds identified, provides a starting point for the future development of novel antiborrelial drugs as well as small-molecule inhibitors that will be helpful for the further dissection of the reaction mechanism.
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Ercan-Fang, Nacide, Miriam R. Taylor, Judith L. Treadway, Carolyn B. Levy, Paul E. Genereux, E. Michael Gibbs, Virginia L. Rath, Younggil Kwon, Mary C. Gannon, and Frank Q. Nuttall. "Endogenous effectors of human liver glycogen phosphorylase modulate effects of indole-site inhibitors." American Journal of Physiology-Endocrinology and Metabolism 289, no. 3 (September 2005): E366—E372. http://dx.doi.org/10.1152/ajpendo.00264.2004.
Анотація:
Phosphorylase is regulated by a number of small-molecular-weight effectors that bind to three sites on the enzyme. Recently, a fourth site referred to as the indole-inhibitor site has been identified. Synthetic compounds bind to the site and inhibit activity. However, the effects of these compounds in the presence of other endogenous effectors are unknown. We have determined the effects of four indole derivative glycogen phosphorylase inhibitors (GPI) on recombinant human liver glycogen phosphorylase a activity. The GPIs tested were all potent inhibitors. However, the endogenous inhibitors (glucose, ADP, ATP, fructose 1-phosphate, glucose 6-phosphate, UDP-glucose) and the activator (AMP) markedly reduced the inhibitory effect of GPIs. Consistent with these in vitro findings, the IC50 for the inhibition of glycogenolysis in cells and the liver drug concentration associated with glucose-lowering activity in diabetic ob/ ob mice in vivo were also significantly higher than those determined in in vitro enzyme assays. The inhibitory effect of indole-site effectors is modulated by endogenous small-molecular-weight effectors of phosphorylase a activity. However, at higher concentrations (10–30 μM), the GPI effect was dominant and resulted in inhibition of phosphorylase a activity irrespective of the presence or absence of the other modulators of the enzyme.
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Yoo, Jihye, Darong Kim, Jiyoung Park, Young-Kook Kim, Hea-Young Park Choo та Hyun Ae Woo. "Novel Small Molecule Inhibitors Targeting the IL-6/STAT3 Pathway or IL-1β". Molecules 27, № 9 (22 квітня 2022): 2696. http://dx.doi.org/10.3390/molecules27092696.
Анотація:
Development of small molecules that inhibit inflammatory cytokines is a desirable strategy for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Following up a previous study, we synthesized 10 novel compounds with a 2,5-diaminobenzoxazole moiety and evaluated their biological activities. Among them, compound 3e showed potent inhibitory activity on Interleukin 6 (IL-6)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling inhibition (71.5%), and 3a showed excellent inhibitory activity on Interleukin 1 (IL-1β) (92.1%). To test in vivo anti-inflammatory activity, compounds 3a and 3e were administered by intraperitoneal (IP) injection after subcutaneous (SC) injection of zymosan A into the right footpad of mice. Inflammation on the footpad was reduced after administration of compounds 3a and 3e. Especially, compound 3a showed a significant ameliorative effect on zymosan-induced inflammation. From the in vivo and in vitro test results, we confirmed that our synthesized compounds are effective on the RA animal model through inhibition of the IL-6/STAT3 signaling pathway. Since drugs developed with small molecule inhibitors have several advantages over biological drugs, further study on these compounds is needed for the development of potent SMI drugs on RA.
Дисертації з теми "Small inhibitory compounds":
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He, Fei, and 贺斐. "In vitro growth inhibitory effects of arsenic trioxide in non-small cell lung cancer with different epidermal growth factor receptormutations." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45860063.
2
Richmond, Oliver H. III. "Extraction, Purification and Evaluation of PRMT5-Inhibitory Phytochemical Compounds for the Treatment of Prostate Adenocarcinoma." DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2019. http://digitalcommons.auctr.edu/cauetds/185.
Анотація:
The development and advancement of prostate cancer is supported by a plethora of genetic and proteomic abnormalities, including events of post-translational modifications. The protein arginine methyltransferase 5 (PRMT5) enzyme regulates epigenetic events of histone modifications and protein post-translational modifications within protein signaling pathways. PRMT5 functions by catalyzing the symmetric dimethylation of terminal arginine residues on target protein substrates. Under abnormal conditions of overexpression and upregulation, PRMT5 methyltransferase activity constitutively drives the growth and proliferation of dysregulated cells. Overexpression or upregulation of PRMT5 correlates with disease progression as observed among numerous cancer types, including breast, colorectal, leukemia, lung, melanoma and prostate cancers. We demonstrated previously that PRMT5 knockdowns attenuated both growth and proliferation of lung and prostatic tumors, in vitro and in vivo. Plants naturally produce chemical toxins as mechanisms of defense against microbial and other biological threats. Human exploitation, consumption and application of agents isolated from plants for therapeutic intervention dates back throughout the millennia. In this study, we extracted, purified and evaluated natural, small, chemical compounds from plant products that antagonize PRMT5 activity in prostate cancer cells. We found that crude and purified extracts of Dendrobium aurantiacum var. denneanum (D. denneanum) plants attenuated prostate tumor growth and proliferation by selective inhibition of PRMT5 methyltransferase activity. These findings establish the first set of natural PRMT5-specific inhibitors reported.
3
García, Reyes Balbina [Verfasser]. "Validation of new Casein Kinase 1 (CK1) small molecule inhibitor compounds and characterization of Inhibitors of Wnt Production (IWPs) as inhibitors of CK1δ / Balbina García Reyes". Ulm : Universität Ulm, 2018. http://d-nb.info/1151938424/34.
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Mohamed, Safwat. "Parallel synthesis of small molecule compound libraries : isoform selective Rho-Kinase inhibitors." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/54300.
Анотація:
The objective of this thesis was to use parallel synthesis to build small molecule libraries of novel compounds with potential as isoform selective type II rho-kinase (ROCK1/2) inhibitors. Considerable effort is ongoing to identify isoform selective ROCK inhibitors, as hyperactivity of the ROCK is implicated in cardiovascular diseases, cancer, diabetes and many other diseases that affect millions of Canadians, and billions of people worldwide. In the absence the extensive structural details of the type II kinase inhibitor binding mode, we have used an empirical approach to the design of type II ROCK inhibitors, based on the conception that such molecules correspond to elongated structures with H-bonding functional elements in their central portion, a motif at one end that mimics the adenine ring in ATP, and a hydrophobic moiety at the other end of the molecule that will interact with an allosteric pocket in the ATP binding region of the kinase. Based on these very general structural requirements, eleven different representative libraries of novel compounds (not described in CAS) were designed and synthesized. In the initial series of compounds, a 2-pyridinone motif was employed as the hinge binding element, and the central portion corresponded to carboxamide substituted oxazoline, oxadiazole, or 2-aminothiazole system, joined through the amide bond to a set of structurally diverse aromatic, heteroaromatic and benzylamine subunits, corresponding to the diversity elements. The preliminary assay results demonstrated that, overall, these compounds were weak and non-selective ROCK1/2 inhibitors when compared to H-1152 as a positive control at 10 μM concentration. However, further structural modification revealed the interest in using an indazole motif as the hinge binder in conjunction with the 2-aminothiazole carboxamide linker. Indeed, more potent activities were observed in the single point assay for a significant portion of the libraries of molecules built around these structural components. Further evaluation of 18 active compounds in a 10-point assay, by Invitrogen, to determine IC50’s revealed that indazole-based inhibitors are active at low micromolar concentrations (1-10 µM), but do not display any significant isoform selectivity.Pharmaceutical Sciences, Faculty of
Graduate
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Strand, Mårten. "The discovery of antiviral compounds targeting adenovirus and herpes simplex virus : assessment of synthetic compounds and natural products." Doctoral thesis, Umeå universitet, Virologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-88186.
Анотація:
There is a need for new antiviral drugs. Especially for the treatment of adenovirus infections, since no approved anti-adenoviral drugs are available. Adenovirus infections in healthy persons are most often associated with respiratory disease, diarrhea and infections of the eye. These infections can be severe, but are most often self-limiting. However, in immunocompromised patients, adenovirus infections are associated with morbidity and high mortality rates. These patients are mainly stem cell or bone marrow transplantation recipients, however solid organ transplantation recipients or AIDS patients may be at risk as well. In addition, children are at higher risk to develop disseminated disease. Due to the need for effective anti-adenoviral drugs, we have developed a cell based screening assay, using a replication-competent GFP expressing adenovirus vector based on adenovirus type 11 (RCAd11GFP). This assay facilitates the screening of chemical libraries for antiviral activity. Using this assay, we have screened 9800 small molecules for anti-adenoviral activity with low toxicity. One compound, designated Benzavir-1, was identified with activity against representative types of all adenovirus species. In addition, Benzavir-1 was more potent than cidofovir, which is the antiviral drug used for treatment of adenovirus disease. By structure-activity relationships analysis (SAR), the potency of Benzavir-1 was improved. Hence, the improved compound is designated Benzavir-2. To assess the antiviral specificity, the activity of Benzavir-1 and -2 on both types of herpes simplex virus (HSV) was evaluated. Benzavir-2 displayed better efficacy than Benzavir-1 and had an activity comparable to acyclovir, which is the original antiviral drug used for therapy of herpes virus infections. In addition, Benzavir-2 was active against acyclovir-resistant clinical isolates of both HSV types. To expand our search for compounds with antiviral activity, we turned to the natural products. An ethyl acetate extract library was established, with extracts derived from actinobacteria isolated from sediments of the Arctic Sea. Using our screening assay, several extracts with anti-adenoviral activity and low toxicity were identified. By activity-guided fractionation of the extracts, the active compounds could be isolated. However, several compounds had previously been characterized with antiviral activity. Nonetheless, one compound had uncharacterized antiviral activity and this compound was identified as a butenolide. Additional butenolide analogues were found and we proposed a biosynthetic pathway for the production of these compounds. The antiviral activity was characterized and substantial differences in their toxic potential were observed. One of the most potent butenolide analogues had minimal toxicity and is an attractive starting point for further optimization of the anti-adenoviral activity. This thesis describes the discovery of novel antiviral compounds that targets adenovirus and HSV infections, with the emphasis on adenovirus infections. The discoveries in this thesis may lead to the development of new antiviral drugs for clinical use.
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Nikjoo, Dariush. "Design and Synthesis of a Small Set of Thiourea-based Compounds as Inhibitors of AChE1 from Mosquitoes." Thesis, Umeå universitet, Kemiska institutionen, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-92551.
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Stoup, Nicolas. "Rôle des domaines EGF de la mucine MUC4 dans la relation structure-fonction et le ciblage thérapeutique du complexe oncogénique MUC4-ErbB2 dans l'adénocarcinome pancréatique." Electronic Thesis or Diss., Université de Lille (2022-....), 2023. http://www.theses.fr/2023ULILS065.
Анотація:
Le cancer du pancréas représente la 4e cause de mortalité par cancer dans le monde. C'est une pathologie fortement létale, dont la survie à 5 ans n'excède pas 10%. Ce pronostic sombre s'explique majoritairement par un diagnostic tardif de la maladie, le plus souvent à des stades métastatiques ou localement avancés (80 % des patients au diagnostic), mais aussi et surtout par un manque de thérapies efficaces. En effet, les thérapies ciblées, notamment celles visant le récepteur ErbB2 (surexprimé dans ce cancer), ainsi que les chimiothérapies conventionnelles (FOLFIRINOX, gemcitabine, Nab-paclitaxel) restent des échecs, constituant des options davantage palliatives que thérapeutiques. En outre, l'incidence de ce cancer est en constance augmentation depuis les années 1980 (+247,7% entre 1980 et 2012), le projetant même à la seconde place des cancers en termes de mortalité d'ici à 2030. Ce problème de santé publique inquiétant nécessite donc d'identifier de nouvelles cibles thérapeutiques afin de proposer de nouveaux traitements alternatifs, plus efficaces pour lutter contre ce cancer. Dans ce sens, la mucine membranaire MUC4 semble être une cible attractive, puisqu'elle est néo-exprimée dès les stades précoces de la maladie et sur-exprimée au cours de la carcinogenèse pancréatique. MUC4 est une large O-glycoprotéine présente à la surface des épithélia, dont le rôle principal est d'assurer l'homéostasie cellulaire, mais qui est fortement dérégulée dans les processus tumoraux. Aussi, MUC4 constitue l'un des seuls partenaires connus d'ErbB2 à la membrane. Des travaux antérieurs du laboratoire avaient identifié une région dans la partie extracellulaire de MUC4 comportant trois domaines de type EGF et impliquée dans l'interaction avec ErbB2. Cependant, avant ces travaux de thèse, rien n'était connu sur la biologie exacte concernant l'interaction entre MUC4 et ErbB2, ni même si les domaines MUC4EGF possédaient une activité biologique intrinsèque pro-tumorale. De même, aucune molécule ciblant efficacement le complexe n'a été testé à ce jour. Le but de ce projet était donc (i) d'élucider les relations structure-fonctions du complexe MUC4-ErbB2, en montrant l'importance des domaines EGF de MUC4 dans l'interaction avec ErbB2 et la promotion tumorale pancréatique, puis (ii) de caractériser les effets d'un premier inhibiteur du complexe MUC4-ErbB2 ciblant la mucine. Ces travaux montrent ainsi que les domaines EGF de MUC4 génèrent toute l'oncogénicité du complexe, en portant l'interaction avec ErbB2 sur des clusters clés identifiés, et en jouant le rôle de facteurs de croissance, capables de promouvoir la prolifération et la migration cellulaires in vitro et in vivo. Nous avons aussi identifié les voies de signalisation spécifiquement activées par le complexe MUC4EGF-ErbB2, ainsi que les marqueurs protéiques spécifiquement up-régulés sous cette interaction. Enfin, nous montrons que le complexe MUC4-ErbB2 peut être ciblé par de petites molécules inhibitrices afin de réduire la prolifération cellulaire cancéreuse in vitro et favoriser la réaccessibilité des thérapies ciblées visant ErbB2. L'ensemble de ces résultats valide ainsi l'intérêt thérapeutique porté par le ciblage du complexe MUC4-ErbB2, et plus particulièrement les domaines EGF de MUC4, comme nouvelle stratégie anti-cancéreuse dans le cancer du pancréasPancreatic cancer is the 4th leading cause of cancer death worldwide. It is a highly lethal pathology, whose 5-year survival does not exceed 10%. This poor prognosis is explained by a late diagnosis of the disease, most often at metastatic or locally advanced stages (80% of patients at diagnosis), but also mainly due to a lack of efficient therapies. Targeted therapies, especially those targeting the ErbB2 receptor (overexpressed in this cancer), as well as conventional therapies (FOLFIRINOX, gemcitabine, Nab-paclitaxel) remain inefficient or fail, representing palliative options more than therapeutic treatments. Moreover, the incidence of this cancer is constantly increasing since the 80's (+247.7% globally between 1980 and 2012), and epidemiologic projections indicate that it will be second leading cause of cancer death by 2030. So, this major public health problem requires the identification of new therapeutic targets in order to propose new alternative treatments, more efficient to reduce the progression of this cancer. In this way, the MUC4 membrane mucin seems to be an attractive target, since it is neo-expressed from the early stages of the disease and over-expressed during pancreatic carcinogenesis. MUC4 is a large O-glycoprotein expressed at the surface of epithelia, whose main role is to ensure cellular homeostasis, but which is strongly deregulated in tumor processes. Also, MUC4 is one of the only known partners of ErbB2 at the membrane. Previous work in the laboratory had identified a region in the extracellular part of MUC4 encompassing three EGF-like domains, and involved in the interaction with ErbB2. However, before this thesis work, nothing was known about the exact biologic modalities of the interaction between MUC4 and ErbB2, as well as if the MUC4EGF domains possessed intrinsic pro-tumoral biological activity. Also, no molecules efficiently targeting the complex have been tested so far. Hence, the aim of this project was (i) to elucidate the structure-function relationships of the MUC4-ErbB2 complex, by enlightening the importance of the EGF domains of MUC4 in the interaction with ErbB2 and the pancreatic tumor promotion, and then (ii) to characterize the effects of the first inhibitory peptide of the MUC4-ErbB2 complex targeting the mucin. This work thus shows that the EGF domains of MUC4 generate the oncogenicity of the complex, by bearing the interaction with ErbB2 on specific hostspots and by playing the role of growth factors, promoting cell proliferation and cell migration both in vitro and in vivo. We have also identified the signaling pathways specifically activated by the MUC4EGF-ErbB2 complex, and the pro-tumoral markers up-regulated by this interaction. Finally, we show that the MUC4-ErbB2 complex can be targeted by small inhibitory molecules to reduce cancer cell proliferation in vitro and to promote the reaccessibility of targeted therapies against ErbB2. Together, these results validate the therapeutic interest of targeting the MUC4-ErbB2 complex, and especially the MUC4EGF domains, as a new anti-cancer strategy in pancreatic cancer
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Garbom, Sara. "A strategy to identify novel antimicrobial compounds : a bioinformatics and HTS approach." Doctoral thesis, Umeå : Department of Molecular Biology, Umeå University, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-900.
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Merkle, Ruth [Verfasser], and Ursula [Akademischer Betreuer] Klingmüller. "Impact of growth factors, therapeutic inhibitors and cytostatic compounds on the response of non-small-cell lung carcinoma cell lines / Ruth Merkle ; Betreuer: Ursula Klingmüller." Heidelberg : Universitätsbibliothek Heidelberg, 2015. http://d-nb.info/1180396413/34.
10
Schmidt, Thomas Christian. "Theoretical Investigations on the Interactions of Small Compounds with their Molecular Environments." Doctoral thesis, 2015. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-127860.
Анотація:
Im ersten Teil dieser Arbeit wird eine Kombination theoretischer Methoden für die strukturbasierte Entwicklung neuer Wirkstoffe präsentiert. Ausgehend von der Kristallstruktur eines kovalenten Komplexes einer Modellverbindung mit dem Zielprotein wurde mit Hilfe von quantenmechanischen und QM/MM Rechnungen die genaue Geometrie des vorausgehenden nicht-kovalenten Komplexes betimmt. Letztere ist der bestimmende Faktor für die Reaktivität des Inhibitors gegenüber der katalytisch aktiven Aminosäure und damit für die Ausbildung einer kovalenten Bindung. Aus diesem Grund wurde diese Geometrie auch für die Optimierung der Substitutionsmusters des Ihnibitors verwendet, um dessen Affinität zum Zielenzyme zu verbessern ohne dass dieser seine Fähigkeit kovalent an das aktive Zentrum zu binden verliert. Die Optimierung des Substitutionsmuster wurde doch Methode des Molekularen Dockings unterstützt, das diese optimal dazu geeignet sind, Bindungsaffinitäten vorherzusagen, die durch eine Modifikation der chemischen Struktur entstehen. Eine Auswahl der besten Strukturen wurde anschließend verwendet, um zu überprüfen, ob die veränderten Moleküle noch genügen Reaktivität gegenüber dem Zielprotein aufweisen. Moleküldynamik Simulationen der neuen Verbindungen haben jedoch gezeigt, dass die veränderten Verbindungen nur so and das Protein binden, dass die Bilung eine kovalenten Bindung zum Enzym nicht mehr möglich ist. Daher wurden in einem weiteren Schritt die Modellverbindungen weiter modifiziert. Neben Änderungen im Substitutionsmuster wurde auch die chemische Struktur im Kern verändert. Die Bindungsaffinitäten wurde wieder mittels Docking überprüft. Für die besten Bindungsposen wurden wieder Simulationen zur Moleküldynamik durchgeführt, wobei diesmal die Ausbildung einer kovalenten Bindung zum Enzyme möglich erscheint. In einer abschließenden Serie von QM/MM Rechnungen unter Berücksichtigung verschiedener Protonierungszustände des Inhibitors und des Proteins konnten Reaktionspfade und zugehörige Reaktionsenergien bestimmt werden. Die Ergebnisse lassen darauf schließen, dass eines der neu entwickelten Moleküle sowohl eine stark verbesserte Bindungsaffinität wie auch die Möglichkeit der kovalenten Bindung an Enzyme aufweist. Der zweite Teil der Arbeit konzentriert sich auf die Umgebungseinflüsse auf die Elektronenverteilung eines Inhibitormodells. Als Grundlage dient ein vinylsulfon-basiertes Moekül, für das eine experimentell bestimmte Kristallstruktur sowie ein theoretisch berechneter Protein Komplex verfügbar sind. Ein Referendatensatz für diese Systeme wurde erstellt, indem der Konformationsraum des Inhibitors nach möglichen Minimumsstrukturen abgesucht wurde, welche später mit den Geometrien des Moleküls im Kristall und im Protein verglichen werden konnten. The Geometrie in der Kristallumgebung konnte direkt aus den experimentellen Daten übernommen werden. Rechnungen zum nicht-kovalenten Protein Komplex hingegen haben gezeigt, dass für das Modellsystem mehrere Geometrien des Inhibiors sowie zwei Protonierungszustände für die katalytisch aktiven Aminosäuren möglich sind. Für die Analyse wurden daher alle möglichen Proteinkomplexe mit der Kristallstruktur verglichen. Ebenso wurden Vergleiche mit der Geometrie des isolierten Moleküls im Vakuum sowie der Geometrie in wässriger Lösung angestellt. Für die Geometrie des Moleküls an sich ergab sich eine gute Übereinstimmung für alle Modellsysteme, für die Wechselwirkungen mit der Umgebung jedoch nicht. Die Ausbildung von Dimeren in der Kristallumgebung hat einen stark stablisierenden Effekt und ist einer der Gründe, warum dieser Kristall so gut wie keine Fehlordungen aufweist. In den Proteinkomplexen hingegen ergibt sich eine Abstoßung zwischen dem Inhibitor und einer der katalytisch aktiven Aminosäuren. Als Ursache für diese Abstoßung konnte die Einführung der Methylaminfunktion ausgemacht werden. Vermutlicherweise führt diese strukturelle Änderung auch dazu, dass der Modellinhibitor nicht in der Lage ist, so wie die Leitstruktur K11777 an das aktive Zentrum des Enzyms zu bindenIn the first part of this work, a combination of theoretical methods for the rational design of covalent inhibitor is presented. Starting from the crystal structure of the covalent complex of a lead compound, quantum mechanical and QM/MM calculations were used to derive the exact geometry of the preceeding non-covalent enzyme inhibitor complex. The geometry of the latter mainly determines the reactivity of the inhibitor against its target enzyme concerning the formation of the covalent bond towards an active site residue. Therefore, this geometry was used as starting point for the optimization of the substitution pattern of the inhibitor such as to increase its binding affinity without loosing its ability to covalently bind to the target protein. The optimization of the chemical structure was supported by using docking procedures, which are best suited to estimate binding affinities that arise from the introduced changes. A screening of the novel substitution patterns resulted in a first generation of model compounds which were further tested for their reactivity against the target. Dynamic simulations on the novel compounds revealed that the orientation that compounds adopt within the active site are such that a covalent interaction with the enzyme is no longer possible. Hence, the chemical structure was further modified, including not only changes in the substituents but also within the core of the molecule. Docking experiments have been conducted to assure sufficiently high binding affinities and to obtain the most favored binding poses. Those have then again been used for dynamic simulations which resulted in structures, for which the bond formation process appeared feasible. A final series of QM/MM calculations considering various protonation states was computed to estimate the reaction energies for the covalent attachment of the inhibitor to the enzyme. The theoretical results indicate a reasonable high inhibition potency of the novel compounds. The second part concentrates on the environmental influences on the electron density of an inhibitor molecule. Therefore, a vinylsulfone-based model compound was selected for which an experimental crystal structure for the pure compound as well as a theoretically determined enzyme-inhibitor complex have been available. To provide reference data for the larger systems, the conformational space of the isolated molecule was screened for favorable geometries which were later compared to those within the crystal and protein surrounding. The geometry of the crystal structure could readily be taken from the experimental data whereas calculations on the protein complex revealed four potential non-covalent complexes exhibiting different arrangements of the molecule within the active site of the protein as well as two possible protonation states of the catalytic dyad. Hence, all four protein complexes have been compared to the crystal structure of the molecule as well as against the more favorable geometries of the isolated molecule being determined within vacuum or aqueous surrounding. Whereas the molecule itself was found to adopt comparable geometries within all investigated environments, the interactions pattern between the crystal surrounding and the protein differed largely from each other. The favorable formation of dimers within the crystal has a strong stabilizing effect and explains the extraordinarily good quality of the crystal. Within the protein however, repulsive forces have been found between the protein and the inhibitor. The origin of the repulsion could be traced back to effect of on of the substituents to the vinyl scaffold. The difference in the chemical structure in comparison to a well known inhibitor might also explain the experimentally found loss of activity for the model compound in comparison to K11777
Книги з теми "Small inhibitory compounds":
1
Woywodt, Alexander, and Diana Chiu. Drug-induced and toxic glomerulopathies. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0082.
Анотація:
Glomerulopathies induced by particular exogenous compounds or molecules include those attributable to toxicity, and those caused by inducing an immune or autoimmune response. Tubules are more commonly the target of toxicity as they absorb and concentrate components of filtrate. Damage to endothelial cells may account for thrombotic microangiopathy in response to calcineurin inhibitors. Endothelial cells are also likely to be the target in drug-induced small vessel vasculitis. Toxicity to podocytes accounts for focal segmental glomerulosclerosis caused by pamidronate and other agents. Chloroquine can cause a remarkable pseudo-storage disorder with inclusions in podocytes that resemble those seen in Fabry disease. The mechanism by which drugs cause minimal change disease, another podocyte disorder, is not known. Membranous nephropathy may be caused by exposure to gold, mercury, and some other drugs; this is antibody mediated and presumably the targets are altered podocyte surface molecules. Inhibitors of the mammalian target of rapamycin (mTOR) cause proteinuria, possibly through effects on vascular endothelial growth factor, inhibitors of which are associated with not only proteinuria (an expected podocyte effect) but also thrombotic microangiopathy (endothelial cell effect). This latter may be through disturbing podocyte-endothelium cross-signaling.
Частини книг з теми "Small inhibitory compounds":
1
Workman, Paul. "Reflections and Outlook on Targeting HSP90, HSP70 and HSF1 in Cancer: A Personal Perspective." In Advances in Experimental Medicine and Biology, 163–79. Cham: Springer International Publishing, 2020. http://dx.doi.org/10.1007/978-3-030-40204-4_11.
Анотація:
Abstract This personal perspective focuses on small-molecule inhibitors of proteostasis networks in cancer—specifically the discovery and development of chemical probes and drugs acting on the molecular chaperones HSP90 and HSP70, and on the HSF1 stress pathway. Emphasis is on progress made and lessons learned and a future outlook is provided. Highly potent, selective HSP90 inhibitors have proved invaluable in exploring the role of this molecular chaperone family in biology and disease pathology. Clinical activity was observed, especially in non small cell lung cancer and HER2 positive breast cancer. Optimal use of HSP90 inhibitors in oncology will likely require development of creative combination strategies. HSP70 family members have proved technically harder to drug. However, recent progress has been made towards useful chemical tool compounds and these may signpost future clinical drug candidates. The HSF1 stress pathway is strongly validated as a target for cancer therapy. HSF1 itself is a ligandless transcription factor that is extremely challenging to drug directly. HSF1 pathway inhibitors have been identified mostly by phenotypic screening, including a series of bisamides from which a clinical candidate has been identified for treatment of ovarian cancer, multiple myeloma and potentially other cancers.
2
Ferrari, Stefania, Federica Pellati, and Maria Paola Costi. "Protein–Protein Interaction Inhibitors: Case Studies on Small Molecules and Natural Compounds." In Disruption of Protein-Protein Interfaces, 31–60. Berlin, Heidelberg: Springer Berlin Heidelberg, 2013. http://dx.doi.org/10.1007/978-3-642-37999-4_2.
3
Kakkar, Rita. "In silico design of PDHK inhibitors: From small molecules to large fluorinated compounds." In Computational Chemistry Methodology in Structural Biology and Materials Sciences, 97–130. Toronto; New Jersey: Apple Academic Press, 2017.: Apple Academic Press, 2017. http://dx.doi.org/10.1201/9781315207544-4.
4
Hoffer, Laurent, Philippe Roche, and Xavier Morelli. "Rational Design of PDZ Domain Inhibitors: Discovery of Small Organic Compounds Targeting PDZ Domains." In Methods in Molecular Biology, 277–89. New York, NY: Springer US, 2021. http://dx.doi.org/10.1007/978-1-0716-1166-1_16.
5
Shuldau, Mikita A., Artsemi M. Yushkevich, Ivan P. Bosko, Alexander V. Tuzikov, and Alexander M. Andrianov. "Generative Autoencoders for Designing Novel Small-Molecule Compounds as Potential SARS-CoV-2 Main Protease Inhibitors." In Communications in Computer and Information Science, 120–36. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-98883-8_9.
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Nock, Berthold A., and Theodosia Maina. "Theranostic Radiopeptides in Nuclear Oncology: Design, Preclinical Screening, and Clinical Translation." In Beyond Becquerel and Biology to Precision Radiomolecular Oncology: Festschrift in Honor of Richard P. Baum, 207–24. Cham: Springer International Publishing, 2024. http://dx.doi.org/10.1007/978-3-031-33533-4_22.
Анотація:
AbstractCancer theranostics is an emerging and exciting field in nuclear medicine, whereby suitably designed radionuclide carriers, after injection to patients, seek and specifically interact with biomolecular targets overexpressed on cancer cells. When a diagnostic radionuclide is applied, molecular imaging with SPECT (gamma emitter) or PET (positron emitter) will reveal tumor lesions, allowing for initial diagnosis and assessment of disease spread and progression. Hence, molecular imaging represents a reliable tool for patient stratification, dosimetry and planning of therapy that follows next with the respective therapeutic radionuclide (beta, Auger electron, or alpha emitter) carrier in an integrated patient-tailored approach. In this way, patients are spared from ineffective and toxic therapies that only impair quality of life without any tangible benefit. Several recent examples have demonstrated the feasibility and efficacy of this strategy. Thus, the advent of radiolabeled somatostatin analogs in the management of neuroendocrine tumors on one hand, and the successful application of prostate-specific membrane antigen inhibitors to diagnose and combat prostate cancer on the other, are two elegant paradigms of this approach.In this chapter, we shall discuss important issues pertaining to the design and preclinical evaluation of peptide-based radioligands, focusing on compound examples developed in our center. The steps to be followed for clinical translation of selected analogs will be also briefly described. Emphasis will be given on the significance of pilot proof-of-principle studies in a small number of patients to guide further efforts toward drug development and registration.
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A. Elrashedy, Ahmed. "Targeting Inhibitor of Enterococcus faecalis: Insights from Comparative Molecular Dynamics and Binding Free Energy Analyses." In Infectious Diseases. IntechOpen, 2024. http://dx.doi.org/10.5772/intechopen.114329.
Анотація:
For the past 50 years, antibiotics that target DNA gyrase have proven to be clinically successful. As a result, the search for novel gyrase inhibitors has intensified due to the rise in bacterial resistance. Since it is absent in eukaryotes yet essential in all bacteria, anti-bacterials target it aggressively. Although quinolones are a clinically approved medication, both Gram-positive and Gram-negative bacteria are developing resistance to them, which compromises their therapeutic efficacy. Thus, it is vital to identify novel compounds that can efficiently inhibit DNA gyrase. A recent experimental study shows that the R-enantiomer of compound 1 was likely to be a more favourable stereoisomer than the R-enantiomer in inhibiting the function of DNA gyrase. However, the molecular mechanisms of its selectivity and inhibition remain elusive. To gain insight into the observed inhibitory effect, molecular dynamics simulations have been employed to investigate the inhibitory mechanism as well as selectivity effect. MD simulation revealed that R-enantiomer selectively targeted the ATP-binding pocket residues, with the 2,4 di chloro carbazole ring’s group interacting into the small hydrophobic pocket provided by Asp 25, arg 26, Ile 182, Val 233, Arg 284, and Ala 286 in DNA gyrase. Finding the residues in the catalytic-binding site may pave the way for the development of a new structure-based inhibitor of highly selective DNA gyrase for the treatment of Enterococcus faecalis infection.
8
Telang, Nitin. "Stem Cell Models: Novel Experimental Approach for Testable Alternatives against Therapy-resistant Breast and Colon Cancer." In Functional Foods for Health Maintenance: Understanding their Role in Cancer Prevention, 384–97. BENTHAM SCIENCE PUBLISHERS, 2023. http://dx.doi.org/10.2174/9789815179217123010018.
Анотація:
Breast and colon cancer represent the leading causes of mortality in developed countries. The treatment options for these organ site cancers differ depending on the status of hormone/growth factor receptors in molecular subtypes that exhibit altered expression of oncogenes/tumor suppressor genes and growth factormediated molecular pathways. Conventional cytotoxic chemo-endocrine therapy traditionally includes the use of anthracyclin, taxol, cisplatin, anti-estrogens, antifolates and DNA anti-metabolites. Additionally, the use of molecular pathway-specific small molecule inhibitors represents evidence-based targeted therapy. Long-term conventional or targeted therapy using pharmacological agents is frequently associated with systemic toxicity, acquired tumor resistance and the emergence of drug-resistant cancer stem cells. These limitations are associated with the progression of the therapyresistant disease. Natural products such as dietary phytochemicals, their respective bioactive agents, botanicals, nutraceuticals and nutritional herbs are widely used in complementary and alternative medicine in women for estrogen-related issues, osteoporosis and breast diseases. Unlike conventional or targeted chemo-endocrine therapeutics, natural products, mainly due to their low systemic toxicity, may not lead to acquired tumor resistance and therefore, represent testable alternatives against therapy-resistant cancer. These aspects emphasize a need to develop reliable experimental approaches, and specific and sensitive biomarkers that facilitate the identification of effective testable alternatives against therapy-resistant cancer. Models for drug-resistant stem cells have been developed and characterized from the parental breast and colon carcinoma-derived cell lines, as well as from the cell lines derived from genetically predisposed colon cancer models. These stem cell models are characterized by the quantifiable expression status of select stem cell-specific cellular and molecular markers.Mechanistically distinct natural products have documented growth-inhibitory effects on parental cell lines. Some of these agents also exhibit stem cell targeted growth inhibitory efficacy. Recognizing clinical evidence for the role of estrogens in breast and colon cancer, future investigations include the development of tumor organoid models of therapyresistant breast and colon cancer from female patient-derived xenografts. These investigations support a scientifically robust rationale to provide clinical translatability for patient-derived preclinical data. This chapter summarizes the evidence relevant to experimental models systems, natural products and efficacy of lead compounds as stem cell-targeted testable alternatives against breast and colon cancer. Collectively, discussed evidence and its clinical relevance support the hypothesis that natural products may benefit patients that are diagnosed for therapy resistant cancers.
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Madala, Sanjay, S. S. V. Kiran K, and Burra V. L. S. Prasad. "In Silico Design of Natural Compound-Derived Novel Inhibitors Against RdRP OF SARS-CoV-2." In Current Trends in Drug Discovery, Development and Delivery (CTD4-2022), 142–54. Royal Society of Chemistry, 2023. http://dx.doi.org/10.1039/9781837671090-00142.
Анотація:
RNA dependent RNA polymerase (RdRp), an important class of nucleic acid polymerases, encoded by RNA viruses such as SARS-CoV-2, has been a major drug target against viral diseases. Among the twenty-nine SARS-CoV-2 encoded proteins, RdRp is referred to as Non-Structural Protein 12 (Nsp12). Obtaining novel RdRp inhibitors is one of the crucial strategies in developing fast therapeutics against COVID-19. The NCI natural compound database containing 250 thousand small molecules was docked against the available 3D structure of SARS-CoV-2 RdRp (PDB ID: 7BV2). The molecules with best docking scores were assessed for their safety through ADMET predictions. Lead molecules that passed all the parameters of ADMET predictions, were subjected to molecular dynamic simulations and binding affinity analysis. This in silico study gave seven antiviral lead compounds that were having better binding affinities than the remdesivir. Their binding affinities ranged from −8.5 to −11.4 kcal/mol which is significantly higher than remdesivir (−7.59 kcal/mol). Besides, these novel antiviral compounds were found to bind between the Finger and Palm domains, restricting or obstructing the template RNA entry and movement, unlike remdesivir which binds at the 3’ end of the nascent RNA near the palm domain. The data indicates stable structures, favorable binding free energies when compared to remdesivir. Besides having better binding affinity, these leads have easy access to the binding pocket unlike the binding site of remdesivir that is in a deep cleft.These advantages of the identified novel compounds demand for immediate in vitro studies.
10
Buechter, Douglas D., and George L. Kenyon. "Inhibitors of Non-Protein Kinases." In Pre-Equilibrium Nuclear Reactions, 164–91. Oxford University PressOxford, 1992. http://dx.doi.org/10.1093/oso/9780198517344.003.0005.
Анотація:
Abstract Small molecule (non-protein) kinases are ubiquitous enzymes that catalyse the transfer of a phosphoryl group, usually from a nucleoside triphosphate donor (e.g. ATP), to a non-protein acceptor molecule. A few kinases are able to utilize pyrophosphate as the phosphoryl donor (e.g. pyrophosphate dependent phosphofructokinase (Reeves et al. 1974)). Non-protein kinases are key enzymes in numerous critical cellular processes. These include the generation of ‘high-energy phosphate ‘ compounds in glycolysis, cellular storage of such compounds, salvage, and de nova synthesis of nucleotides/ nucleosides for nucleic acid synthesis and phospholipid biosynthesis. Inhibitors of non-protein kinases are of importance in mechanistic and enzymological investigations and in the elucidation of their physiological roles. Because these enzymes catalyse critical biochemical reactions, cellular growth and metabolism are often highly dependent upon their activity. As a result, many of these enzymes are attractive targets for anticancer and antiviral agents. Of particular importance is the design of inhibitors that are selective either for certain isozymes of one organism (e.g. fetal versus adult isozymes) or for enzymes from different organisms (e.g. viral versus host enzymes). The design of such inhibitors is facilitated by an understanding of the mechanism and structure of the enzyme at the molecular level. Thus investigations of the three-dimensional structure, kinetics, chemical mechanism, and active site residues of kinases are of considerable importance in modern drug design.
Тези доповідей конференцій з теми "Small inhibitory compounds":
1
Yang, Jiang, and Xintong Wang. "Effect of Thio-Chemicals Molecular Structure for Corrosion Inhibition in CO2 Corrosive Environments." In SPE International Conference on Oilfield Chemistry. SPE, 2023. http://dx.doi.org/10.2118/213847-ms.
Анотація:
Abstract Carbon dioxide often exists in oil and gas fields, and CO2 flooding is also increasingly used to enhance oil recovery. CO2 is highly corrosive to steel in oilfield fluid. The effective and economical method for controlling corrosion is the addition of corrosion inhibitors for carbon steel materials. Small thio-compounds have been found effective to enhance corrosion inhibition of imidazoline inhibitors. In this study, several small thio-derivatives inhibitor including mercaptoethanol (ME), thiourea (TU), and mercaptoacetic acid (TGA) and 2-mercaptobenzimidazole (MBI) were compared to inhibit the CO2 corrosion. They were used as synergists to enhance corrosion inhibition of oleic imidazoline (OIM) for carbon steel at 60 °C in CO2-saturated brine. The corrosion inhibition was investigated by weight loss and electrochemical methods. The surface was characterized by scanning electron microscopy (SEM). The mechanism of corrosion inhibition was studied by quantum chemical calculations. The results show that the MBI with the aromatic group gave the best corrosion inhibition than that of ME, TGA, and TU. The surface characterization showed no pitting and localized corrosion at 10 ppm of inhibitor. The model of interaction is proposed that OIM is protonated and coupled with MBI by electrostatic attraction to co-adsorb on the carbon steel surface. MBI adsorbs on Fe by a bidentate binding-N-S-bridge connection, which effectively prevents the corrosion of carbon steel in the CO2 environment. The research provides a structure-properties relationship of thio-chemicals to develop more effective corrosion inhibitors.
2
Yang, Jiang, and Xintong Wang. "Effect of Thio-Chemicals Molecular Structure for Corrosion Inhibition in CO2 Corrosive Environments." In SPE International Conference on Oilfield Chemistry. SPE, 2023. http://dx.doi.org/10.2118/213848-ms.
Анотація:
Abstract Carbon dioxide often exists in oil and gas fields, and CO2 flooding is also increasingly used to enhance oil recovery. CO2 is highly corrosive to steel in oilfield fluid. The effective and economical method for controlling corrosion is the addition of corrosion inhibitors for carbon steel materials. Small thio-compounds have been found effective to enhance corrosion inhibition of imidazoline inhibitors. In this study, several small thio-derivatives inhibitor including mercaptoethanol (ME), thiourea (TU), and mercaptoacetic acid (TGA) and 2-mercaptobenzimidazole (MBI) were compared to inhibit the CO2 corrosion. They were used as synergists to enhance corrosion inhibition of oleic imidazoline (OIM) for carbon steel at 60 °C in CO2-saturated brine. The corrosion inhibition was investigated by weight loss and electrochemical methods. The surface was characterized by scanning electron microscopy (SEM). The mechanism of corrosion inhibition was studied by quantum chemical calculations. The results show that the MBI with the aromatic group gave the best corrosion inhibition than that of ME, TGA, and TU. The surface characterization showed no pitting and localized corrosion at 10 ppm of inhibitor. The model of interaction is proposed that OIM is protonated and coupled with MBI by electrostatic attraction to co-adsorb on the carbon steel surface. MBI adsorbs on Fe by a bidentate binding-N-S-bridge connection, which effectively prevents the corrosion of carbon steel in the CO2 environment. The research provides a structure-properties relationship of thio-chemicals to develop more effective corrosion inhibitors.
3
Drew, Allison, Lorna Mitchell, Nathalie Rioux, Kerren Swinger, Scott Ribich, Suzanne Jacques-O'hagan, Trupti Lingaraj, et al. "Abstract 5376: Identification of the first small molecule PRMT6 inhibitor tool compound." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-5376.
4
Odarenko, K. V., O. V. Salomatina, N. F. Salakhutdinov, M. A. Zenkova, and A. V. Markov. "SEARCH FOR REGULATORY GENES AND SMALL-MOLECULAR INHIBITORS OF THE HIGHLY AGGRESSIVE PHENOTYPE OF GLIOBLASTOMA." In X Международная конференция молодых ученых: биоинформатиков, биотехнологов, биофизиков, вирусологов и молекулярных биологов — 2023. Novosibirsk State University, 2023. http://dx.doi.org/10.25205/978-5-4437-1526-1-279.
Анотація:
Four sets of RNA-sequencing data were re-analyzed, and INHBA and VEGFC were found to be novel regulators of the highly aggressive mesenchymal phenotype of glioblastoma; their expression was validated in vitro. In the library of amide derivatives of soloxolone, the compound Jil-46 was identified, which blocked glial‑mesenchymal transition (GMT), inhibited stemness, and induced apoptosis in U87 glioblastoma cells.
5
Wu, Jianghong, Jie Qian, Lihui Lu, and Haiching Ma. "Abstract 5547: Exploration of selective small molecule compounds as caspase inhibitors for treatment of oral mucositis caused by cancer therapy." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-5547.
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Panić, Jovana J., Snežana M. Papović, Teona Teodora V. Borović, Nikolet A. Cako Baganj, Sanja D. Belić, Slobodan B. Gadžurić, and Milan B. Vraneš. "The hydration and antimicrobial properties of selected imidazole-based ionic liquids with a homologous series of chloride oxyanions." In 2nd International Conference on Chemo and Bioinformatics. Institute for Information Technologies, University of Kragujevac, 2023. http://dx.doi.org/10.46793/iccbi23.124p.
Анотація:
The aim of this work was to get a detailed insight into the ion’s interactions along with the structure-making/structure-breaking tendency that has been retrieved through the perusal of calculated parameters from volumetric measurements for aqueous solutions of three newly synthesized ionic liquids: 1-butyl-3-methylimidazolium chlorite, 1-butyl-3-methylimidazolium chlorate and 1-butyl-3-methylimidazolium perchlorate. Further, the antimicrobial activity of synthesized and commercial (1-butyl-3-methylimidazolium chloride) ionic liquids on certain strains of bacteria and fungi was obtained. Antimicrobial tests were performed using the in vitro microdilution method against isolated strains of Escherichia coli, Staphylococcus aureus, Bacillus cereus bacteria, and the fungus Candida guilliermondii. This method is a rapid, quantitative method for the determination of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) using small amounts of samples (µl) and test compound. Based on the obtained results, the influence of the homologous series of chloride oxyanions on hydration and antimicrobial properties of imidazole-based ionic liquids will be discussed.
7
Kosaka, Hiromichi, Yasuo Watanabe, Michihiro Maemoto, Masamori Sugawara, Miwa Watanabe, Yoko Ono, Yoshisuke Nakasato, Masahiro Matsubara, and Ryuichiro Nakai. "Abstract A155: Small molecule metabolic inhibitors, compound A and the derivatives specifically inhibit the cell growth of Ewing's sarcoma cells harbor EWS-FLI1 in vitro and in vivo." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1535-7163.targ-15-a155.
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Chen, L. C., and C. Y. Yang. "Case Report: A Rare Epidermal Growth Factor Receptor (EGFR) H773L/V774M Compound Mutation in Advanced Non-Small Cell Lung Cancer with Poor Response to EGFR Tyrosine Kinase Inhibitor." In American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a6993.
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Li, Fengzhi, Xiang Ling, Shousong Cao, and Qiuying Cheng. "Abstract 4525: Discovery and characterization of a small chemical compound that shows exceptional antitumor activity and targets multiple antiapoptotic proteins in the inhibitor of apoptosis (IAP) and Bcl-2 families." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-4525.
Звіти організацій з теми "Small inhibitory compounds":
1
Chamovitz, Daniel A., and Zhenbiao Yang. Chemical Genetics of the COP9 Signalosome: Identification of Novel Regulators of Plant Development. United States Department of Agriculture, January 2011. http://dx.doi.org/10.32747/2011.7699844.bard.
Анотація:
This was an exploratory one-year study to identify chemical regulators of the COP9 signalosome. Chemical Genetics uses small molecules to modify or disrupt the function of specific genes/proteins. This is in contrast to classical genetics, in which mutations disrupt the function of genes. The underlying concept is that the functions of most proteins can be altered by the binding of a chemical, which can be found by screening large libraries for compounds that specifically affect a biological, molecular or biochemical process. In addition to screens for chemicals which inhibit specific biological processes, chemical genetics can also be employed to find inhibitors of specific protein-protein interactions. Small molecules altering protein-protein interactions are valuable tools in probing protein-protein interactions. In this project, we aimed to identify chemicals that disrupt the COP9 signalosome. The CSN is an evolutionarily conserved eight-subunit protein complex whose most studied role is regulation of E3 ubiquitinligase activity. Mutants in subunits of the CSN undergo photomorphogenesis in darkness and accumulate high levels of pigments in both dark- and light-grown seedlings, and are defective in a wide range of important developmental and environmental-response pathways. Our working hypothesis was that specific molecules will interact with the CSN7 protein such that binding to its various interacting proteins will be inhibited. Such a molecule would inhibit either CSN assembly, or binding of CSN-interacting proteins, and thus specifically inhibit CSN function. We used an advanced chemical genetic screen for small-molecule-inhibitors of CSN7 protein-protein interactions. In our pilot study, following the screening of ~1200 unique compounds, we isolated four chemicals which reproducibly interfere with CSN7 binding to either CSN8 or CSN6.