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 17 of 17 for “"Fragment Screening"”.
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Targeting an E3 ubiquitin ligase Siah1 and a cysteine protease SENP1 using SPR and DSF-based fragment screening
This dissertation presents fragment screening studies against two human proteins Siah1 and SENP1, which function in post-translational modification pathways. Siah1 is an E3 ubiquitin ligase that functions as a scaffold to transfer ubiquitin bound to an E2 ubiquitin-conjugating enzyme to a substrate …
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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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Fragment-based approaches to probe the surface of the VHL E3 ligase
… well as discovering novel binders and pockets by fragment screening. A competition assay for probing interactions in the substrate recognition domain of the VHL E3 ligase was developed by fluorine nuclear magnetic resonance. Thorough characterisation of the fluorinated reporter molecules revealed …
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Structural studies to inform antimicrobial drug discovery and the basis of immunity against T6 effectors
… drug target. The results of structural and fragment-screening efforts presented here inform early stage drug discovery efforts.<br/>The structure of the PabC protein (4-amino-4-deoxychorismate lyase, EC: 4.1.3.38) from the Gram-negative pathogen Pseudomonas aeruginosa was also determined. …
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Structure- based inhibitor design for key enzymes of <em>Tryposoma brucei</em>
… different techniques like in silico virtual screening, NMR lead-like fragment screening and HTS were used. For <em>Tb</em>UGP a very first drug-like, competitive inhibitor with a pIC50 of 3.53±0.04 and a Hill slope of 1.1±0.1 was discovered. Additionally this thesis describes the …
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Investigation of mass spectrometry approaches for aiding fragment-based drug discovery
… use in drug discovery, particularly in fragment-based drug discovery (FBDD). The work described in this thesis focuses broadly on the application of MS techniques to aid FBDD campaigns. In Chapter 1, an overview of the strengths and limitations of MS in FBDD is presented. In Chapter 2, …
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Understanding and Targeting the FGF-2/S6K2 Signal Pathway in Small Cell Lung Cancer Towards the Development of Novel Anti-Cancer Treatments.
… sites on the XIAP mRNA, and perform novel drug fragment screening with hnRNP A1.
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Structure-Based Drug Design Against a Biosecurity Pathogen
… bound structure. X-ray crystallography-based fragment screening is then applied, identifying a large number of binding fragments, bound not only to the active site but also an allosteric site. We show that binders inhibit enzyme activity, with promise for further development. Lastly, using …
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Structural studies of paired PHD finger-bromodomain chromatin-binding modules: targeting epigenetic readers with chemical probes
… natural binding partner can be combined with fragment screening to gauge future optimization of small molecules. The first section described the disclosure of the binding mode of the H3 histone tail by the PHD zinc finger of BAZ2A. A crystal structure of the complex of BAZ2A with the H3 10-mer …
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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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Hijacking Cancer Signaling: First-in-class JPRK-targeting Ligands for Fibrolamellar Hepatocellular Carcinoma
Described herein is a drug screening project focused on an oncoprotein beginning with in silico fragment screening against an un-drugged target and concluding with a collaboration to evaluate single digit nanomolar potent and >500-fold selective drug candidates in patient derived xenografts. …
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Targeting infectious species by Structure-guided Fragment-based Drug Discovery and in silico approach
… novel and validated targets are exploited using fragment-based drug discovery (FBDD) and in silico approaches to design unconventional antibiotics that could extend the scope of current treatment options and reverse some of the effects of living in a post-antibiotic era. Firstly, three biological …
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Target Identification and Mechanism of Action Studies in Folate Metabolism in Kinetoplastids
… pterin derivatives for bead coupling led to a fragment screening campaign being carried out on QDPR in leishmania major. Working through a triage workflow, two moderately potent fragments were identified, showing inhibition against LmQDPR. Through structure-free optimization strategies, greater …
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Synthesis of Structurally Diverse N-Substituted Quaternary Carbon Containing Small Molecules and Their Application as Novel Starting Points for Drug Discovery
… uneven exploration of chemical space. Whilst fragment-based screening has proven a fruitful strategy for identifying novel bioactive small molecules, in a similar vein to high-throughput screening approaches, obstacles within this paradigm have been recognised. This relates to a lack of …
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Targeting final steps of sugar nucleotide biosynthetic pathway against <i>Aspergillus fumigatus</i>
… (HsAGM1). In addition, using crystallography and fragment screening, I have demonstrated that a resveratrol scaffold can fit into a surface pocket on domain IV of the AfAGM1 protein. The binding mode of resveratrol suggests possibility of developing selective allosteric inhibitors of AfAGM1. In …
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Biophysical and Biochemical Screening Approaches for Antimicrobial Drug Discovery Targeting S. aureus ClpP
… of conventional antibiotics drug discovery screening approaches, and transitions to modern era structure or fragment based screening approaches. The merits and challenges of such approaches of targeting a well conserved bacterial protease (ClpP) are discussed along with dissertation aims …