Between Dec 19, 2024 and Jan 2, 2025, datasets can be submitted to DRUM but will not be processed until after the break. Staff will not be available to answer email during this period, and will not be able to provide DOIs until after Jan 2. If you are in need of a DOI during this period, consider Dryad or OpenICPSR. Submission responses to the UDC may also be delayed during this time.
 

Structural Biology for Drug Design: Applications in Two Systems

Loading...
Thumbnail Image

Persistent link to this item

Statistics
View Statistics

Journal Title

Journal ISSN

Volume Title

Title

Structural Biology for Drug Design: Applications in Two Systems

Published Date

2016-08

Publisher

Type

Thesis or Dissertation

Abstract

Two projects comprise this dissertation; both are focused on using the technique of protein X-ray crystallography to understand the molecular interactions that small molecules make with proteins and the subsequent exploitation of these interactions to design better substrate or inhibitor molecules. The human Histidine Triad Nucleotide Binding Proteins (hHints) are a family of nucleotide phosphoramidases and acyl nucleotide hydrolases, coming to the forefront of research interest due to the role of hHint1 in the activation of sofosbuvir, the blockbuster Hepatitis C treatment. In the hHint project, protein-ligand complexes are examined in order to establish a structural reaction trajectory, including the first captured covalent intermediate for this enzyme, and to describe a general strategy for designing a prodrug moiety that will be activated by hHint1. The Lethal Factor (LF) component of the tripartite toxin produced by Bacillus anthracis is a zinc metalloproteinase. To date, there is no approved inhibitor of this protein for the treatment of anthrax infection partially due to difficulty in obtaining selectivity over endogenous metalloproteinases. A series of hydroxamate-containing inhibitors revealed that Domain 3 of LF is responsive to the molecule in the active site and that certain states of Domain 3 may be energetically favorable to target. Furthermore, a ligand-induced extension of the canonical binding area was discovered, paving the way for the development of more specific LF inhibitors.

Description

University of Minnesota Ph.D. dissertation. August 2016. Major: Medicinal Chemistry. Advisor: Barry Finzel. 1 computer file (PDF); vi, 207 pages.

Related to

Replaces

License

Collections

Series/Report Number

Funding information

Isbn identifier

Doi identifier

Previously Published Citation

Other identifiers

Suggested citation

Maize, Kimberly. (2016). Structural Biology for Drug Design: Applications in Two Systems. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/182796.

Content distributed via the University Digital Conservancy may be subject to additional license and use restrictions applied by the depositor. By using these files, users agree to the Terms of Use. Materials in the UDC may contain content that is disturbing and/or harmful. For more information, please see our statement on harmful content in digital repositories.