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Please use this identifier to cite or link to this item: http://hdl.handle.net/11375/27328
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dc.contributor.advisorMelacini, Giuseppe-
dc.contributor.authorMohamed, Hebatallah-
dc.date.accessioned2022-01-29T02:32:43Z-
dc.date.available2022-01-29T02:32:43Z-
dc.date.issued2021-
dc.identifier.urihttp://hdl.handle.net/11375/27328-
dc.description.abstractAllosteric regulation is essential to control biological function. In addition, allosteric sites offer a promising venue for selective drug targeting. However, accurate mapping of allosteric sites remains challenging since allostery relies on often subtle, yet functionally relevant, structural, and dynamical changes. In this thesis, a new toolset of NMR-based methodologies known as T-CHESCA and CLASS-CHESCA are proposed to identify key allosteric sites, using isoform 1 of the exchange protein activated by cAMP (EPAC1) as the model system. The T-CHESCA imposes changes on the fast-exchanging active/inactive states of the protein through temperature changes while the CLASS-CHESCA imposes changes through variations in the spin-active nuclei involved in pairwise correlations of residues. The residue ensembles identified by the CHESCA methods were found in previously identified EPAC allosteric sites. EPAC1 has also been identified as a promising drug target for cardiovascular diseases and based on structural analogues of a novel EPAC1-specific inhibitor called I942, the next aim of the work was to generate a quantitative structure activity relationship model (QSAR). The QSAR model was able to predict the affinity of a promising inhibitor with enhanced potency and inhibitory activity compared to I942 which was confirmed through competition assays, 15N-1H HSQC experiments, saturation transfer difference (STD) and chemical shift projection analysis (CHESPA).en_US
dc.language.isoenen_US
dc.titleIdentification of Core Allosteric Networks and Development of QSAR Models for EPAC1en_US
dc.typeThesisen_US
dc.contributor.departmentChemistry and Chemical Biologyen_US
dc.description.degreetypeThesisen_US
dc.description.degreeMaster of Science (MSc)en_US
dc.description.layabstractExchange proteins activated by cyclic AMP (EPAC) are cAMP sensors with several functions in cellular pathways. EPAC has been found to be associated with multiple diseases such as cardiovascular diseases. This study aims to first identify the main residues involved in the regulation of EPAC1 activity and then develop a predictive model that is able to find promising and selective inhibitors for the protein. The two approaches can then be useful in designing effective modulators of EPAC1 for the treatment of cardiovascular diseases such as cardiac hypertrophy.en_US
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