Global ETD Search
Search theses and dissertations gathered from participating repositories worldwide. Every result links back to the library that holds it. No account is needed.
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Showing 1 to 20 of 22 for “"Fragment based drug discovery"”.
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Investigation of mass spectrometry approaches for aiding fragment-based drug discovery
The use of mass spectrometry (MS)-based techniques to study protein structure dynamics is a relatively new field, with seminal developments such as nanoelectrospray ionization (nano-ESI) and traveling-wave ion mobility-mass spectrometry (TWIM-MS) MS being introduced only around twenty-five and …
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Studies within Fragment-Based Drug Discovery: Library Synthesis and Hit-to-Lead Optimisation
… projects aimed at addressing challenges within fragment-based drug discovery. The first project describes efforts towards utilising synthetic methodology to address deficiencies within fragment screening collections. This involved the development of a modular, robust and scalable route to access …
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Targeting infectious species by Structure-guided Fragment-based Drug Discovery and in silico approach
… several human pathogens have developed multidrug resistance and few new antibiotics are being discovered. In addition to the challenge of the emergence of antibiotic resistance, the bacterial population also harbours mechanisms that increase pathogenicity and virulence by tolerating …
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Targeting Mycobacterium abscessus Infection in Cystic Fibrosis: A Structure-guided Fragment-based Drug Discovery Approach
… emergence of Mycobacterium abscessus, a highly drug-resistant non-tuberculous mycobacterium, which causes life-threatening infections in people with chronic lung conditions like cystic fibrosis. This opportunistic pathogen is refractory to treatment with standard anti-tuberculosis drugs and most …
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A Fragment-Based Drug Discovery Approach for the Development of Selective Inhibitors of Protein Kinase CK2
Over the last twenty years, fragment-based drug discovery (FBDD) has emerged as a highly successful way to provide lead compounds for subsequent optimisation into drug candidates. Initial hits usually exhibit lower potency than those identified by more traditional techniques, such as …
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To Design and Develop Semi-Saturated and Unsaturated Bicyclic Heterocycles for Fragment-Based Drug Discovery (FBDD) Campaigns
The concept of Fragment-Based Drug-Discovery (FBDD) seeks to overcome current issues associated with High-Throughput Screening (HTS) for the identification of novel hits, which are ultimately elaborated into leads and drug candidates. This thesis focuses on the preparation of either novel or …
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Triazole-linked reduced amide isosteres: An approach for the fragment-based drug discovery of anti-Alzheimer's BACE1 inhibitors and NH-assisted Fürst-Plattner opening of cyclohexene oxides
… we used an originally designed microtiter plate-based screening to discover 4 triazole-linked reduced amide isosteres that showed modest (single digit micromolar) BACE1 inhibition. Our ligands were designed based on a very potent (single digit nanomolar) isopththalamide ligand from Merck. We …
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Fragment synthesis: pharmacophore and diversity oriented approaches
This thesis explores two approaches to fragment-based drug discovery. First, protein target CK2 was chosen due to its importance in the cancer phenotype. A literature fragment, NMR154L, proved to be a promising compound for fragment development, due to its binding at the interface site of the …
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Radical methods for the synthesis of aliphatic amines
… chemical space, making the reaction relevant for fragment-based drug discovery.
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Structural basis for the function of the transcriptional regulator KstR from Mycobacterium tuberculosis
… cholesterol degradation pathway, is a potential drug target in Mtb. In this study, KstR has been biochemically and structurally characterised as a basis for discovering new drugs targeting the cholesterol metabolism in Mtb. The interactions between KstR and cognate DNA or ligands have been …
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Synthesis of Partially Saturated Bicyclic Heteroaromatics: sp3-Enriched Scaffolds for Drug Discovery
… years have seen an expansion beyond the more druggable biological targets into novel areas of biological space. However, drug discovery campaigns against these challenging targets have been afflicted with low hit rates during screening campaigns and high levels of candidate attrition during …
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Inhibition of enzymes from the non-mevalonate pathway using fragment-based approaches
… in this thesis is focussed on the application of fragment-based approaches to identify novel scaffolds as chemical probes against two essential target proteins in the non-mevalonate pathway (MEP), 1-deoxy-D-xylulose 5-phosphate synthase (DXS) from *D.radiodurans* and 1-deoxy-D-xylulose-5-phosphate …
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Approaches Towards the Inhibition of Anti-Apoptotic Proteins
… the well-conserved ATP-binding site: -Using a Fragment-Based-Drug-Discovery (FBDD) approach twelve small molecule inhibitors of CK2 were developed. The lead molecule, 3l, inhibited the catalytic activity of CK2α by binding in the cryptic αD pocket with a Kd of 4 μM. 3l stopped proliferation of …
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Synthesis of a Diverse and Three-Dimensional Fragment Collection and The Development of a Novel Platform for Antibody Dual Functionalisation
… of a library of small molecules suitable for fragment-based screening. Over the past two decades, fragment-based drug discovery (FBDD) has emerged as a powerful strategy for early-stage drug discovery. However, despite its many successes, FBDD often suffers from the lack of synthetic …
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DNA-PKcs/ Artemis Complex in DNA Double-Strand-Break Repair: Cryo-EM and Biochemical Studies
… of my PhD project focuses on the preliminary drug discovery of Artemis/ DNA Ligase IV complex. An intrinsically disordered Artemis C-terminal peptide interacts with DNA Ligase IV through concerted folding, showing a site that can be most easily targeted by small molecules. Therefore, during my …
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Characterisation of the Essential t<sup>6</sup>A tRNA Modification Enzymes and Evaluation as a Potential Novel Antimicrobial Target
… a small number of compounds in a high-throughput fragment-based drug discovery assay. Some of these have been shown to potentially affect the ATPase activity of the enzymes.</p>
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Small molecule inhibition of immunoregulatory protein-protein interactions
… address this limitation, we utilized two binding-based approaches, a unique peptidomimetic fragment library and high-throughput small-molecule microarrays to design and discover molecules that target three important immunoregulatory PPIs: the DQ8-insulin complex, the KEAP1-Nrf2 complex, and the …
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A fragment-based approach towards understanding molecular recognition of 4’-phosphopantetheine adenylyltransferase from Mycobacterium abscessus
… in this thesis details the application of a fragment-based approach targeting 4’-phosphopantetheine adenylyltransferase (PPAT) from Mycobacterium abscessus (Mabs). A fragment screen of the Abell laboratory 960-member library was conducted by Dr Sherine Thomas (Department of Biochemistry, …
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Cryo-EM as a Tool to Study the Diverse Interactome of Ku 70/80 in NHEJ and Beyond
… and chemotherapy, I aimed to develop a drug discovery pipeline to examine the druggability of protein-protein interactions (PPIs) in NHEJ, given their diversity and crucial role in pathway progression, as seen from our cryo-EM work. I focused on one interaction, that of Ku with XLF. …
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Targeting Trehalose and Methylglucose Lipopolysaccharide Biosynthetic Pathways in M. tuberculosis - Structural and Functional Characterisation, and Early-Stage Drug Discovery of OtsA and Rv3030
… inhibition. Furthermore, a structure-guided, fragment-based drug-discovery exercise was carried out against the target, which led to identification of fragment hits that have an inhibitory effect on the activity of the enzyme. Polymethylated polysaccharides (PMPSs) are complex intracellular …
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