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Novel computational methods for biomechanistic and metallodrug discovery

Wragg, Darren 2019. Novel computational methods for biomechanistic and metallodrug discovery. PhD Thesis, Cardiff University.
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The growth of molecular modelling and free-energy calculations for drug discovery and development have provided a platform for the work undertaken in this thesis. The known affinity of certain metals for biological targets, such as gold/thiol affinity, has guided this research on the characterisation of interactions involved in both protein function inhibition and non-canonical DNA sequence stabilisation. The ability to calculate microsecond timeframes of our biological targets has allowed for greater understanding of these mechanisms at a molecular level. The research in this thesis is organised into two sections. The first part covers the mechanism of permeation and inhibition of AQP3 via a number of molecular dynamic techniques, such as umbrella sampling and metadynamics. The effects of a Au(III) complex on the protein conformation of AQP3 upon metal binding were investigated using steered molecular dynamics. The pH induced gating mechanism of AQP7 and its effect on both water and glycerol permeation was studied to understand the protein conformational changes involved. The second part investigates the stabilising effect of Au(I) N-heterocyclic carbenes (NHCs) on G-quadruplex DNA structures. The metadynamics calculated free-energy results were then compared to FRET melting assay results to determine the mechanism of interaction. Throughout this work we have shown how the use of in silico methods can enhance our mechanistic knowledge and understanding of biological systems, helping validate and explain experimental results, and vice versa. We have used state of the art molecular dynamics techniques, either rarely or not yet used for such complex systems, thus, furthering the knowledge of our group, and through published work, the wider scientific community

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Date of First Compliant Deposit: 24 September 2019
Last Modified: 25 Sep 2019 11:34

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