Targeting Aspartate Transcarbamoylase: A Versatile Approach to Multispecies Drug and Herbicide Discovery

Xiaochen Du

Research output: ThesisThesis fully internal (DIV)

167 Downloads (Pure)

Abstract

This thesis primarily focuses on the identification and study of new drug target essential in nucleic acid metabolism, specifically the catalytic step supported by aspartate transcarbamoylase – the second step of pyrimidine biosynthesis6. Interference with this pathway may generate new drugs aimed at various diseases, including malaria, tuberculosis, human cancer, as well as herbicides in plant growth.
The goal of this thesis is to design small molecules based on in vitro experiments and X-ray crystallography that target the aspartate transcarbamoylase (ATCase) of malaria, and aims to evaluate this class of small molecules (named the BDA series) against other species, including but not limited to tuberculosis, humans, and herbicides.With results varying from the nanomolar to micromolar, the optimization methods for further development of BDA series to improve inhibitory properties are under consideration. Moreover, new series inhibitor design and discovery cannot be ignored. Although analysis of homology modeling generated structure binding modes of this series’ compounds has supported the hypothesis of the existence of an allosteric pocket within these pathogens, the X-ray structures are still needed to demonstrate the details between the proteins and inhibitors, which would also support the design of further new series of inhibitory candidates.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • University of Groningen
Supervisors/Advisors
  • Groves, Matthew, Supervisor
  • Dömling, Alex, Supervisor
Award date30-Apr-2024
Place of Publication[Groningen]
Publisher
DOIs
Publication statusPublished - 2024

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