Dissertations / Theses on the topic 'Inhibition covalente'
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Fındık, Volkan. "Simulations atomistiques de la réaction d’acétylation d’amines et de l’inhibition covalente de l’enzyme Phosphoinositide 3-kinase (PI3K)." Electronic Thesis or Diss., Université de Lorraine, 2022. http://www.theses.fr/2022LORR0266.
Targeted Covalent Inhibitors (TCIs) hold great promise for search of new drugs. They offer a number of potential advantages over traditional reversible inhibitors, such as extended residence time, increased potency, and the ability to make modifications for effective design. Kinase inhibitors are the most common examples of TCIs. Phosphoinositide 3-kinase (PI3K) enzymes are important drug targets in oncology as they are involved in the signaling pathway for many cellular functions such as growth control, metabolism and translation initiation. Lysine (Lys) residues have gained increasing interest as an alternative for targeted covalent inhibition. Recently, the first selective and irreversible inhibitors with ester groups as electrophilic head targeting the Lys779 residue and covalently inactivating the PI3Kδ enzyme were reported. The main objective of this thesis is to elucidate the mechanism of the covalent inhibition of PI3Kδ by these ester inhibitors in order to assist future design of new inhibitors with superior activities. Prior to the mechanistic studies on the enzyme, initially, we performed ab initio and DFT calculations on the model reaction between methylamine and methyl, phenyl and p-NO2 phenyl acetates in aqueous solution. The same model systems were then studied by the "dual-level" QM/MM molecular dynamics approach. For the “low-level” option, PM3/TIP3P umbrella sampling QM/MM simulations were applied for the sampling. The obtained structures were then used to obtain perturbative corrections to the free energy with a “high-level” QM region at the M06-2X/6-311+G(d,p) level. The results show that thefirst step involves the formation of the zwitterionic tetrahedral intermediate. Then, for sufficiently electrophilic esters, such as the p-NO2 derivative, the reaction proceeds by dissociation of the zwitterion as an ion pair, followed by proton transfer leading to the formation of the expected products. We, then, employed similar computational tools to shed light on the mechanistic aspects of the enzyme. First, an active site model of the enzyme was built through classical molecular dynamics simulations. Then, ONIOM QM:QM approach at the M06-2X/6 -31+G(d,p):PM6 level was applied to get possible reaction mechanisms in this active site. These calculations guided us to refine the reaction mechanisms in enzyme environment which globally confirm the steps obtained from the small model system. We finally used this information to approach a dynamic QM/MM study on the enzyme using the same“dual-level” protocol established for the small model system, which allowed us to obtain the free energy profile of the inhibition mechanism of PI3Kδ for p-NO2 derivative of the ester inhibitor. The calculated barrier is in good agreement with the available experimental kinetic data, which validates the proposed theoretical approach and the obtained mechanisms. Through the elucidation of the inhibition mechanism of previously experimentally tested compounds, our study paves the way for the discovery of new inhibitors with improved activity with the help of theoretical chemistry tools
Akbar, Abdullah. "Design, Synthesis and Evaluation of Covalent Inhibitors for Tissue Transglutaminase and Factor XIIIa." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39645.
Belghazi, Maya. "Etude de modifications covalentes de protéines par spectrométrie de masse Maldi-Tof et Esi-Tof." Palaiseau, Ecole polytechnique, 2001. http://www.theses.fr/2001EPXX0030.
Erdmann, Alexandre. "Conception, synthèse et caractérisation de nouveaux inhibiteurs de méthyltranférases d'ADN à visée anticancéreuse." Thesis, Toulouse 3, 2015. http://www.theses.fr/2015TOU30270.
Epigenetic is defined as the study of heritable changes in the genes expression without altering the DNA sequence. Two main processes are implicated in this field, the histones modifications and the DNA methylation. By introducing an acetyl or a methyl group on the histone tails or by methylation of DNA, the chromatin state is modified and the gene expression is controlled. Aberrant epigenetic modifications are associated with several diseases, in particular with cancer. In cancer cells, the whole DNA is hypomethylated, thus promoting genome instability, while the promoter region is hypermethylated, inducing silencing of these genes. Overall, these observations indicate that DNA methylation is a central epigenetic process in cancerogenesis. Since DNA methylation is reversible, it is possible to target the methylation process in order to reactivate tumor suppressor genes. The DNA methyltransferases (DNMTs), the enzymes responsible for DNA methylation, use the SAM co-factor at specific CpG sites to product 5-methylcytosine. Three main isoforms (DNMT1, DNMT3A and DNMT3B) are described to ensure efficient methylation process during replication. Two families of DNMT inhibitors already exist, the nucleosidiques analogues are cytidine derivatives and are toxic molecules because of their incorporation into DNA, and the non-nucleosidic analogues are less toxic but also less potent. Our strategy of drug design is based on docking study and high throughput screening (HTS) information. First, novel potent derivatives of reference inhibitors are designed from molecular modelling. Then, three different families of compounds from HTS are described with appropriate structure-activity relationship studies. Mechanistic information on DNA methylation process are described through the discovery of a reactive inhibitor of DNMT3A. The study on a family of hydrazone derivatives of gallic acid is depicted and shows its selectivity for DNMT3A, compared to DNMT1, based on docking study. An alternative chemical pathway to diaminopyrimidines is described and extended to the synthesis of quinazolone in order to synthesize new quinazoline derivatives as potent inhibitors of DNMT. Promising informations are described in this thesis to enrich epigenetic knowledge of tumor genesis and to provide new molecules for anticancer therapy
Ueda, Tsuyoshi. "Development of Covalent Inhibitors and Drug Screening using Ligand-Directed NASA Chemistry." Doctoral thesis, Kyoto University, 2020. http://hdl.handle.net/2433/253248.
0048
新制・課程博士
博士(工学)
甲第22412号
工博第4673号
新制||工||1729(附属図書館)
京都大学大学院工学研究科合成・生物化学専攻
(主査)教授 浜地 格, 教授 森 泰生, 教授 生越 友樹
学位規則第4条第1項該当
Doctor of Philosophy (Engineering)
Kyoto University
DGAM
Vermeer, Lydia Maria Mexas. "Covalent modification and inhibition of tyrosine hydroxylase by 3,4-dihydroxyphenylacetaldehyde, an endogenously produced neurotoxin relevant to Parkinson's disease." Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/1923.
Tay, Sew Wah. "Factors affecting the thrombin inhibiting activity of heparin when immobilised to hydrogels by covalent bonding." Thesis, Massachusetts Institute of Technology, 1986. http://hdl.handle.net/1721.1/16490.
MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE.
Bibliography: leaves 157-166.
by Sew-Wah Tay.
Sc.D.
Bourgeois, Karine. "Towards in vitro Pharmacokinetic Assessment of Novel Targeted Covalent Inhibitors for Human Tissue Transglutaminase." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39472.
CAMPANER, ELENA. "A new covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action." Doctoral thesis, Università degli Studi di Trieste, 2017. http://hdl.handle.net/11368/2908180.
Serrano, Aparicio Natalia. "Inhibition studies on the human 20S proteasome: molecular insights from a computational approach." Doctoral thesis, Universitat Jaume I, 2022. http://dx.doi.org/10.6035/14122.2022.684242.
Programa de Doctorat en Química Teòrica i Modelització Computacional
CASTELLI, SILVIA. "QUANTITATIVE PROTEOMIC APPROACHES TO STUDY DRUG MECHANISM OF ACTION." Doctoral thesis, Università degli Studi di Milano, 2023. https://hdl.handle.net/2434/950653.
Scholtes, Jan Felix [Verfasser], and Oliver [Akademischer Betreuer] Trapp. "Chiral induction in stereodynamic catalysts by non-covalent interactions : ligand design, supramolecular self-recognition, deracemization and enantioselective self-inhibition / Jan Felix Scholtes ; Betreuer: Oliver Trapp." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1188564129/34.
Engdahl, Cecilia. "Selective inhibition of acetylcholinesterase 1 from disease-transmitting mosquitoes : design and development of new insecticides for vector control." Doctoral thesis, Umeå universitet, Kemiska institutionen, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-134625.
Qu, Bingqian [Verfasser], and Stephan [Akademischer Betreuer] Urban. "Hepatitis B Virus X protein-mediated transcription of covalently closed circular DNA and its inhibition by blocking neddylation / Bingqian Qu ; Betreuer: Stephan Urban." Heidelberg : Universitätsbibliothek Heidelberg, 2020. http://d-nb.info/1223176142/34.
Bordessa, Andrea. "Design, synthesis and structural evaluation of peptidomimetics towards foldamers, PNAs and non covalent inhibitors of the 20S proteasome." kostenfrei, 2008. http://www.opus-bayern.de/uni-regensburg/volltexte/2009/1112/.
Ortega, Varga Laura. "Innovative inhibition strategy against functional structural transitions of essential pathogenic factors : Computational applications to Malarial and Neurotransmitter targets." Electronic Thesis or Diss., Sorbonne université, 2019. http://www.theses.fr/2019SORUS455.
This PhD project describes the design of inhibitors of two essential malaria enzymes and of novel modulators of specific nicotinic acetylcholine receptors (nAChRs). Plasmodium vivax subtilase SUB1 is required for parasite egress. We focused our efforts on the design of reversible covalent inhibitors of PvSUB1. We performed covalent docking of potential peptide and peptidomimetic candidates and studied peptide cyclization. Several peptides have shown activity in the submicromolar range and could be resolved after co-crystalization. Plasmodium falciparum lactate dehydrogenase is critical for parasite metabolism. We targeted it by design on the basis of inhibitory cofactor analogs. We have built a combinatorial library aiming to bridge the cofactor and the substrate binding site, while avoiding affecting the human isoenzymes. We screened it in silico and selected about fifty molecules that are under synthesis for ex vivo testing. We also targeted α5 subunit containing nAChRs to address addiction. A multidisciplinary approach has been established. It uses an AChBP engineered chimera, which structure was solved in complex with the first known 5 ligands. This structure, and two comparative modeling models were used to perform in silico screening. A cation-π interaction definition was introduced in the FlexX software and side chain flexibility was allowed in the binding site. An interactive pipeline was developed for the analysis of the virtual screening results and hit molecules have been confirmed by STD-NMR experiments. Deep neural networks models were also built to assess on- and off-target bioactivity prediction in a panel of nAChRs and putative off-targets
GALBIATI, ANDREA. "DESIGN AND SYNTHESIS OF NOVEL ENZYME INHIBITORS AS ANTIPROLIFERATIVE COMPOUNDS WITH ANTIPROTOZOAL AND ANTICANCER ACTIVITY." Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/827428.
Mutthamsetty, Vinay. "Design and Synthesis of Amino Acid-based Inhibitors Against Key Enzymes." University of Toledo / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1513014525316672.
Zerhouni, Marwa. "Mécanismes de résistance aux thérapies ciblées dans le mélanome cutané métastatique et les syndromes myélodysplasiques : Caractérisation et validation préclinique de composés innovants." Electronic Thesis or Diss., Université Côte d'Azur, 2020. http://www.theses.fr/2020COAZ6008.
Cutaneous metastatic melanoma (CMM) and myelodysplastic syndromes (MDS) are two incurable cancers developing resistance to their reference antitumor treatments. Cells resistant to these therapies are characterized by a metabolic reprogramming which profoundly influences and promotes tumor progression. Therefore, inhibition of metabolic pathways seems to be a promising therapeutic strategy to overcome resistance in these two pathologies.The two teams involved in this thesis project have a long-lasting collaboration in the field of cancer. In this context and in partnership with the Nice Institute of Chemistry, our two teams have developed innovative compounds targeting intra-cellular energy balances and the AMPK pathway. Among these compounds, we were more specifically interested in AICAR (Acadesine). Screening efficiency and structure-activity studies enabled us to optimize the structure of our compounds. Based on their solubility, their stability, and their ability to induce tumor cells death, we have identified HA 344 as a lead compound.This study describes the characterization and validation of a new covalent inhibitor, HA 344, derived from Acadesine, effective on CMM and MDS cell lines either sensitive or resistant to their reference treatment but also on CMM and MDS patient cells. By combining click chemistry, proteomics, and metabolomics approaches, we have identified this molecule as a covalent inhibitor of two different metabolic hubs within cancer cells. HA 344 inhibits the final and rate-limiting step of glycolysis through its covalent binding to the pyruvate kinase M2 (PKM2) enzyme, and concurrently blocks the activity of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme of de novo guanylate synthesis. HA 344 efficiently eliminates tumor growth of BRAF inhibitor sensitive- and resistant-CMM cells both in vitro and in vivo. Thus, this specific mechanism of action of HA 344 provides potential therapeutic avenues not only for patients with CMM but also a broad range of cancers
Hua, Tzu-Yu, and 華梓佑. "Structures of NP exonuclease-inhibitor complex reveal the unique inhibition mechanism by a covalent bond between cysteine and inhibitor." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/b95fht.
國立交通大學
生物資訊及系統生物研究所
105
The Nucleoprotein exonuclease ( NP exonuclease ) of Lassa virus is involved in viral genomic RNA encapsidation, viral RNA synthesis and host immune evasion. NP exonuclease is constituted by N-terminal and C-terminal domains, of which the main function of N-terminal domain is to capture the 5' cap of mRNA in the host cell for carrying out transcription and replication of its own viral RNA; the C-terminal domain of NP exonuclease belongs to the DEDDh exonuclease family. The C-terminal domain is used to degrade pathogen associated molecular patterns generated by infecting host cells, like RNA; and thus further make IRF-3 transcription factor unable to enter the nucleus to induce interferon synthesis of immune system. If the highly conserved amino acids in the C-terminal domain are mutated, it will cause a decline in ability for Lassa virus to escape the host immune system, in other words, the C-terminal domain plays an important role in virus infections; hence the C-terminal domain of NP exonuclease can be used as a target for anti-viral drug research. In this study, we found the inhibitor candidates for NP exonuclease by literature reviews and computational molecular docking program. Through the nuclease activity assay, we identified several inhibitors with high inhibition efficiency, such as ATA、PCMPS、PHMB、PV6R and NCI35. We also determined the crystal structures of apo-NP exonuclease protein structure and NP exonuclease-PCMPS complex in which PCMPS was covalently bound to the cysteine ( C409 ) in the C-terminal domain, indicating that the covalent bond is critical to suppress the activation of NP exonuclease. Our biochemical experiments and two crystal structures reveal a unique inhibitory mechanism of PCMPS through covalent linkage to the NP exonuclease, and this work could be applied to the development of antiviral drugs.
Burstein, Gayle Diane. "An investigation of the irreversible inhibition of human N[superscript ω], N[superscript ω]- dimethylarginine dimethylaminohydrolase (DDAH1)." Thesis, 2014. http://hdl.handle.net/2152/31281.
text
Ni, Kevin Chen. "Role of Covalent Modification of Hyaluronan with Inter-Alpha Inhibitor Heavy Chains During Acute Lung Injury." Diss., 2019. http://hdl.handle.net/1805/19248.
The extracellular matrix (ECM) provides a structural and signaling platform for cells that comprise various organs, playing a critical role in tissue maintenance, injury, and repair. Hyaluronan (also known as hyaluronic acid, HA) is a ubiquitous ECM polysaccharide consisting of a repeating disaccharide backbone that can be covalently modified by the heavy chains (HC) of the serum protein inter-alpha-inhibitor (IαI) during inflammation. Known as the only covalent modification of HA, the HC linking of HA is exclusively mediated by the inflammation-induced secreted enzyme TNFα-stimulated gene-6 (TSG-6). Mice deficient for HC-HA formation, due to the lack of either TSG-6 or IαI, display reduced survival during systemic lipopolysaccharide (LPS)-induced endotoxic shock and its associated acute lung injury. We therefore hypothesized that HC-HA should play an important protective role against acute lung injury induced by intratracheal LPS or Pseudomonas aeruginosa (PA) gram-negative bacteria. We also identified that lung instillation of LPS or PA caused rapid induction of lung parenchymal HC-HA that was largely cleared during resolution of injury, indicative of a high rate of HA turnover and remodeling during reversible lung injury. However, using TSG-6 knockout mice, we determined that HC-HA exerted minimal protective effects against intratracheal LPS or PA-induced acute lung injury. To better address the differential roles of HC-HA during systemic versus localized intratracheal exposure to LPS, we characterized and compared the induction of HC-HA in plasma and lung in these two models. While lung parenchymal HC-HA formed in both injury models, intravascular HC-HA and TSG-6 were exclusively induced during systemic LPS exposure and were associated with improved outcomes, including decreased number of circulating neutrophils and plasma TNFα levels. Our results suggest that LPS induces HC-HA formation in various tissues depending on the route of exposure and that the specific intravascular induction of HCHA during systemic LPS exposure may have a protective role during endotoxic shock.
Correy, Galen Joseph. "Structure, function, evolution and inhibition studies of the organophosphate detoxifying enzyme αE7." Phd thesis, 2018. http://hdl.handle.net/1885/262300.
Kuo, Chin-Jung, and 郭瑾融. "A non-covalent small inhibitor blocking β-tubulin:CCT-β complex induces apoptosis and suppresses migration and invasionin CL1-5 cells." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/yj45b7.
國立臺灣大學
生化科學研究所
107
Previously, we reported the protein-protein interaction (PPI) between β-tubulin and CCT-β complex as a potential anti-cancer chemotherapeutic target. Through virtual screening, a compound 3112210 from Sigma-Aldrich compound bank was identified to be a reversible inhibitor of the PPI by docking into hot spots on this PPI interface of β- tubulin. In this study, 3112210 was tested on a highly metastatic non-small cell lung cancer (NSCLC) cell line, CL1-5. The co-IP experiments showed that, in 3112210-treated cancer cells, β-tubulin and CCT-β complex was disrupted. Furthermore, 3112210 caused CL1-5 cell death through ER stress and apoptosis. In addition to verifying its toxicity toward CL1-5, we performed migration and invasion assays using dosage at about IC20. The results indicated that 3112210 also inhibited cancer cell migration and invasion, and MMP-2, -9 were also inhibited. These anti-metastatic effects were endowed via integrin- related pathways and EMT transcriptional factors, as demonstrated by western blot experiments. To sum, 3112210 is a novel non-covalent inhibitor for β-tubulin:CCT-β complex in CL1-5 lung adenocarcinoma cells to induce cancer cell death and impeded cell metastasis.