Investigation of mass spectrometry approaches for aiding fragment-based drug discovery

The use of mass spectrometry (MS)-based techniques to study protein structure dynamics is a relatively new field, with seminal developments such as nanoelectrospray ionization (nano-ESI) and traveling-wave ion mobility-mass spectrometry (TWIM-MS) MS being introduced only around twenty-five and fifteen years ago, respectively. However, MS methods have not yet found widespread use in drug discovery, particularly in fragment-based drug discovery (FBDD). The work described in this thesis focuses broadly on the application of MS techniques to aid FBDD campaigns. In Chapter 1, an overview of the strengths and limitations of MS in FBDD is presented. In Chapter 2, native MS and IM-MS were used to explore the effect of DMSO, a common solvent used in fragment screening on protein size and stability in the gas-phase. In Chapter 3, native MS was used to study the structure of the EthR-DNA complex, a tuberculosis target, and to screen fragments against a protein-DNA interaction for the first time. In Chapter 4, native MS and IM-MS were used to study the structure and interactions of the antibacterial target CoaB and its ligands, including potential fragment inhibitors. In Chapter 5, native MS was used to study the protein-protein interaction between Aurora A, an anticancer target, and TPX-2, and its inhibition using chemical compounds. In Chapter 6, the overall conclusions and outlook of this project are presented. Overall, these studies demonstrate the utility of native MS approaches in providing complementary information to other biophysical techniques regarding protein structure and interactions in FBDD campaigns.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Chan, Daniel

Advisor dc:contributor.advisor

• Abell, Chris

• mass spectrometry
• native mass spectrometry
• fragment based drug discovery

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/a68d6cfe-8c6c-4510-abc4-7deddd67bc20/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.56067

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/308976