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Drug discovery through combination of computational screening and design, chemical synthesis and biological evaluations

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dc.contributor.advisor Ojima, Iwao en_US
dc.contributor.author Berger, William Theodore en_US
dc.contributor.other Department of Chemistry. en_US
dc.date.accessioned 2017-09-20T16:51:56Z
dc.date.available 2017-09-20T16:51:56Z
dc.date.issued 2013-12-01 en_US
dc.identifier.uri http://hdl.handle.net/11401/77087 en_US
dc.description 349 pg. en_US
dc.description.abstract A long-standing problem with the use of conventional cancer chemotherapy is the inherent lack of tumor specificity. Tumor-targeting drug-delivery systems (TTDS) have since been explored to overcome this deficiency. These drug conjugates can deliver potent cytotoxic drugs specifically to tumors and tumor cells with minimal systemic toxicity. Among various tumor-targeting molecules discussed, Designed Ankyrin Repeat Proteins (DARPins) represent a new approach to tumor targeting. In particular, DARPins targeting CD326 Epithelial Cell Adhesion Molecule (EpCAM) receptors provide an effective cancer target, as EpCAM is critical to the regulation of cellular matrix composition and overall cancer aggressiveness. Botulism is a human illness caused by the bacterium Clostridium botulinum which results in fatal flaccid paralysis and eventual respiratory failure. Clostridium botulinum produces botulinum neurotoxins (BotNTs), which by themselves are considered by the CDC to be potential Category A bioterrorism weapons. The light chain protease domain of BotNTs efficiently cleaves SNARE proteins which in turn regulates neurotransmitter release in motor neurons, resulting in the inhibition of neuronal transmission. Discussed is the use of a novel footprint-based virtual screening to identify compounds with inhibitory activity against BotNTA-LC catalytic activity. Fatty acid binding proteins (FABPs), have recently been identified as intracellular transporters for the endocannabinoid anadamide (AEA). Furthermore, animal studies by others have shown that elevated levels of endocannabinoids result in beneficial pharmacological effects on stress, pain and inflammation and also ameliorate the effects of drug withdrawal. Accordingly a novel α -truxillic acid derivative (SB-FI-26) was synthesized and assayed for its inhibitory activity against FABP5. Additionally, we found SB-FI-26 to act as a potent anti-nociceptive agent with mild anti-inflammatory activity in mice, which strongly supports our hypothesis that the inhibition of FABPs and subsequent elevation of anandamide is a promising new approach in drug discovery. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Chemistry en_US
dc.subject.other Berger W. T., Botulism, FABP, Medicinal Chemistry, SB-FI-26, SB-T-1214 en_US
dc.title Drug discovery through combination of computational screening and design, chemical synthesis and biological evaluations en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Simmerling, Carlos en_US
dc.contributor.committeemember Boon, Elizabeth en_US
dc.contributor.committeemember Deutsch, Dale. en_US

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