Rational Optimization of Small Molecules for Alzheimer’s Disease Premortem Diagnosis
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| Language: | English |
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The Ohio State University / OhioLINK
2012
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=osu1338325484 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu1338325484 |
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oai_dc |
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NDLTD |
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English |
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NDLTD |
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Biochemistry Biology Biophysics Medical Imaging Molecular Biology Molecular Chemistry Molecules Neurobiology Neurosciences Physical Chemistry Alzheimer's Disease premortem diagnosis PET imaging tau protein amyloid QSAR computational chemistry polarizability dispersion forces selectivity ligand binding |
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Biochemistry Biology Biophysics Medical Imaging Molecular Biology Molecular Chemistry Molecules Neurobiology Neurosciences Physical Chemistry Alzheimer's Disease premortem diagnosis PET imaging tau protein amyloid QSAR computational chemistry polarizability dispersion forces selectivity ligand binding Cisek, Katryna Rational Optimization of Small Molecules for Alzheimer’s Disease Premortem Diagnosis |
| author |
Cisek, Katryna |
| author_facet |
Cisek, Katryna |
| author_sort |
Cisek, Katryna |
| title |
Rational Optimization of Small Molecules for Alzheimer’s Disease Premortem Diagnosis |
| title_short |
Rational Optimization of Small Molecules for Alzheimer’s Disease Premortem Diagnosis |
| title_full |
Rational Optimization of Small Molecules for Alzheimer’s Disease Premortem Diagnosis |
| title_fullStr |
Rational Optimization of Small Molecules for Alzheimer’s Disease Premortem Diagnosis |
| title_full_unstemmed |
Rational Optimization of Small Molecules for Alzheimer’s Disease Premortem Diagnosis |
| title_sort |
rational optimization of small molecules for alzheimer’s disease premortem diagnosis |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2012 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1338325484 |
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AT cisekkatryna rationaloptimizationofsmallmoleculesforalzheimersdiseasepremortemdiagnosis |
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1719430707044941824 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu13383254842021-08-03T06:05:17Z Rational Optimization of Small Molecules for Alzheimer’s Disease Premortem Diagnosis Cisek, Katryna Biochemistry Biology Biophysics Medical Imaging Molecular Biology Molecular Chemistry Molecules Neurobiology Neurosciences Physical Chemistry Alzheimer's Disease premortem diagnosis PET imaging tau protein amyloid QSAR computational chemistry polarizability dispersion forces selectivity ligand binding <p>Alzheimer’s disease is a debilitating, progressive neurodegenerative disorder that affects a large percentage of the elderly population. Currently, there is no definitive premortem diagnosis and no cure. These protein aggregates accumulate for many years before the onset of clinical symptoms; therefore, their in situ detection would be an invaluable tool for early premortem diagnosis. Because radiolabeled small molecules used for whole brain imaging, such as those used for PET imaging, have the advantage of tracking the spatiotemporal pattern of molecular targets, this approach has tremendous utility for neurodegenerative disorders. More specifically, the detection of tau-bearing neurofibrillary tangles is especially promising as the amount and spatiotemporal pattern of tau-aggregate deposition is the gold standard of postmortem disease assessment, as it correlates with loss of neurons. The main challenge in the development and optimization of a tau-selective imaging agent is the structure of these aggregates, which adopts a cross-beta-sheet of interdigitating monomers. </p><p>Although multiple scaffold classes have been reported to bind cross-ß-sheet structure, their mechanism of binding and their ability to selectively bind different aggregates of varying protein composition are not well understood. There are no crystal or NMR structures that would reveal the atomic-level binding modes of this interaction. Most small molecule development studies focus on iterative structure-activity relationship modifications and testing of known scaffolds, such as the benzothiazole dye and commonly used tissue staining agent Thioflavin T. Even though quantitative structure activity relationship studies have been employed to investigate amyloid-binding compounds, these retrospective studies have not elucidated any novel compound molecular properties that could explain the mechanism of interaction. Moreover, these studies have not rationalized the binding activity or selectivity of cross-ß-sheet-binding ligands in the context of computational binding models. </p><p>The project described herein is a ligand-based quantitative structure activity relationship approach to identify descriptors of binding affinity and selectivity for two series of over fifty closely related benzothiazole derivatives and indolinones reported to displace ThT fluorescent probe from synthetic aggregates composed of tau and ß-amyloid peptide. This is a novel computational approach in that it seeks to elucidate binding affinity, selectivity as well as binding site density in the context of existing experimental and computational data. I developed a two-step regression analysis for the identification of two-dimensional “global” descriptors of ligand potency and selectivity, in conjunction with a three-dimensional analysis for the identification of volumetric “local” regions for the optimization of R-group substituents of potent and selective ligands. The resulting models were statistically robust and predictive and provided clear guidelines for ligand optimization. For the indolinone series, the model was successful in predicting novel potent analogues, which upon synthesis and testing were shown to be very promising candidates for further preclinical studies.</p> 2012-06-27 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1338325484 http://rave.ohiolink.edu/etdc/view?acc_num=osu1338325484 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |