자료유형  

 학위논문

Control Number  

0015490230

International Standard Book Number  

9781687922670

Dewey Decimal Classification Number  

543

Main Entry-Personal Name  

Gee, Clifford T.

Publication, Distribution, etc. (Imprint  

[Sl] : University of Minnesota, 2017

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2017

Physical Description  

337 p

General Note  

Source: Dissertations Abstracts International, Volume: 81-04, Section: B.

General Note  

Advisor: Pomerantz, William C. K.

Dissertation Note  

Thesis (Ph.D.)--University of Minnesota, 2017.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약Protein-protein interactions (PPIs) play a vital role in biological processes but are difficult to target therapeutically. However, targeting PPIs is an important challenge because their dysregulation is linked to many various disease states including cancers and neurological disorders. While high throughput screening (HTS) has long been the standard method for drug discovery, fragment-based screening (FBS) has emerged as a promising alternative strategy due to its greater coverage of chemical space with smaller library sizes. Successful cases like Vemurafenib and Venetoclax, continue to bolster FBS efforts. Though many techniques, including X-ray crystallography, surface plasmon resonance, and thermal shift assays, have all been used as screening tools, the central hypothesis of this dissertation is that 19F NMR is a powerful and time efficient FBS tool that is complementary to existing tools and is useful for characterizing proteins and small molecule ligands. Protein-Observed Fluorine NMR Spectroscopy (PrOF NMR) due to its high speed, lack of background signals, environmental sensitivity, is an ideal method to use for both ligand discovery and characterization of ligand-protein interactions. Herein, we describe the application of PrOF NMR to two proteins in particular, the KIX domain of CBP/p300 which is part of a larger transcriptional activation complex, and the first bromodomain of BrdT, an epigenetic "reader" protein that has been validated as a target for male contraception. We demonstrate the use of PrOF NMR as a primary screening tool for KIX, identifying key pharmacophores for KIX binding. We also demonstrate the use of PrOF NMR for characterizing ligand-protein interactions, uncovering a new binding site in KIX, distinct from its two native transcription factor binding sites. Validation of hits from other screening campaigns can also be followed via PrOF NMR, and the quantitative information obtained can be used to guide the structure-activity relationship (SAR) process for further ligand development. Beyond ligand discovery in proteins, fluorine magnetic resonance can also be applied as an imaging and oximetry tool. Given the sensitivity of fluorine and its applications in both biophysical and biomedical contexts, fluorine magnetic resonance serves as a new tool for small-molecule screening, ligand development, and oxygen sensing.

Subject Added Entry-Topical Term  

Biochemistry

Subject Added Entry-Topical Term  

Organic chemistry

Subject Added Entry-Topical Term  

Analytical chemistry

Added Entry-Corporate Name  

University of Minnesota Chemistry

Host Item Entry  

Dissertations Abstracts International. 81-04B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:567517