Development of NMR methods to facilitate drug discovery and formulation

2006 2006

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Abstract (summary)

Abstract The goals of this thesis are to apply NMR experiments to problems important in drug discovery and development to (1) probe interactions between small drug molecules and proteins, (2) characterize interactions between drug-like molecules and excipients, and (3) study aspects of surfactant chemistry.

The first of these goals is addressed by applying the epitope mapping experiments, NOESY, STD, and BPPSTE, to map the interactions between the R and S enantiomers of propranolol and α1 acid glycoprotein (AGP). In addition to mapping the interactions between the propranolol enantiomers and AGP, these experiments allowed the comparison of optimal experimental parameters for each type of experiment.

The second goal of this thesis is addressed by applying a newly developed PFG diffusion experiment, the gradient phase encoded spin-lock (GraPES), and ROESY experiments to study the binding of drug-like molecules to an important class of pharmaceutical excipients, cyclodextrins. The GraPES experiment is useful for determining contacts between cyclodextrins and simple small molecules of moderate binding strength. The ROESY experiment can be used to determine the contacts with cyclodextrins for more complex molecules. In addition the GraPES experiment can be applied to ligand-protein binding systems to suppress the protein background. The results of the GraPES experiment further led us to examine the techniques used to analyze diffusion binding interaction or epitope mapping results.

The third goal of this thesis is addressed by (1) following the degradation of polysorbate 20 under accelerated degradation conditions and (2) characterizing monorhamnolipid mixtures. A calibration curve was developed to allow the quantitation of the extent of degradation of polysorbate 20. In addition, this method allows identification of the degradation products. The structures of several new monorhamnolipids were elucidated using a combination of NMR and mass spectrometry. Also, the average pKa of a mixture of monorhamnolipids was determined to be 4.39 ± 0.06 by NMR pH titration. The results of this pH titration indicated that the previous literature average pKa corresponded to a change in rhamnolipid supramolecular structure and not the pKa of the carboxylic acid moiety.

Indexing (details)

Analytical chemistry
0486: Analytical chemistry
Identifier / keyword
Pure sciences; Drug discovery; Epitope mapping; NMR; Overhauser effect
Development of NMR methods to facilitate drug discovery and formulation
Becker, Bridget A.
Number of pages
Publication year
Degree date
School code
DAI-B 67/11, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
Desaire, Heather; Larive, Cynthia
University of Kansas
University location
United States -- Kansas
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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