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Developing and applying novel Enhanced Sampling simulation techniques for Drug Discovery, Design, and Delivery

Evans, Rhys; (2022) Developing and applying novel Enhanced Sampling simulation techniques for Drug Discovery, Design, and Delivery. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The development process for new drug therapies is expensive, involved, and essential, and computational methods play an ever-increasing role in many of the steps. This thesis presents an exploration into the use of computational techniques and simulation-based methods to aid the pharmaceutical development process. Focussing on the usage of enhanced sampling techniques including metadynamics, replica-exchange, and combined methods, it investigates their application through various stages of the drug discovery pipeline. It is divided into three main projects, each targeting a specific aspect of the process. Firstly, by establishing and analysing a database of cryptic sites in publicly available protein structures, it provides a significant resource in the field of drug discovery. Cryptic sites are those binding sites that are only visible in the presence of the ligand and exploiting them has the potential to dramatically increase the druggable proteome. The second project involves the development and testing of three novel methods for absolute binding free energy calculations within fragment-based drug design. Intended as a proof of concept, it is demonstrated that these methods each have a specific area in which they excel, with wide applicability in the lead optimisation phase. Finally, this thesis presents an investigation into the use of self-assembling peptides for drug delivery and biomaterial applications. Drug encapsulation promises wide ranging benefits, but is often achieved using synthetic polymers to create self-assembling micelles. In collaboration with experimentalists at UCL, I explore the viability of creating histidine-based peptidic vesicles by studying their self-assembled structures and the impact of sequence changes on their resultant properties.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Developing and applying novel Enhanced Sampling simulation techniques for Drug Discovery, Design, and Delivery
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10150028
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