Development of small molecule inhibitors of protein nucleic acid interactions with the use of computer-aided drug discovery tools
department or school: Science, Faculty of
data provider: DSpace
degree campus: UBCV
creator: Radaeva, Mariia
issued: 2025-09-30T07:00:00Z
issued: 2024
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: In the realm of the development of cancer therapeutics, a significant portion of the human proteome, including over 1600 transcription factors (TFs), is classified as "undruggable". These proteins, often being critical drivers in various cancers, present unique challenges due to their intricate nature and complex interactions with nucleic acids. Despite these obstacles, they offer a very significant therapeutic potential, necessitating innovative approaches for their exploitation in cancer treatment. This thesis showcases the development and application of Computer-Aided Drug Discovery (CADD) in overcoming the challenges associated with targeting proteins that have been previously deemed âundruggableâ. Through detailed case studies, it reveals the strategic use of CADD in three distinct scenarios: - For the androgen receptor (AR), CADD leverages the existing experimental data to design novel inhibitors with unique chemotypes; - in case of the RNA-binding protein Lin28, CADD orchestrates the entire drug discovery process, from the identification of the binding site to the optimization of lead compounds; - for targeting HOXB13, a relatively uncharted factor, CADD facilitates navigating selectivity challenges, showcasing the adaptability of these tools in unlocking previously unattainable drug targets. Collectively, these three projects illustrate how CADD can assist in the development of inhibitors that disrupt of protein-nucleic acid interactions across various protein families and stages of drug discovery and addressing numerous CADD challenges. Additionally, this work demonstrates that the utility of CADD is deeply intertwined with experimental validation. By seamlessly integrating computational modeling with experimental workflow, this thesis not only introduces novel methodologies for targeting challenging proteins involved into transcription but also highlights the synergistic potential of advancements in both computational and experimental domains. The outcomes…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/89202
note: DEVELOPMENT OF SMALL MOLECULE INHIBITORS OF PROTEIN NUCLEIC ACID INTERACTIONS WITH THE USE OF COMPUTER-AIDED DRUG DISCOVERY TOOLS by Mariia Radaeva B.Sc., University of Bath, 2018 M.Sc., University of British Columbia, 2020 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Bioinformatics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) August 2024 © Mariia Radaeva, 2024 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Development of Small molecule Inhibitors of Protein Nucleic Acid Interactions With The Use Of Computer-Aided Drug Discovery Tools submitted by Mariia Radaeva in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Bioinformatics Examining Committee: Artem Cherkasov, Professor, Bioinformatics, UBC Supervisor Xuesen Dong, Associate Professor, Urologic Sciences, UBC Co-Supervisor Ivan Sadowski, Professor, Biochemistry and Molecular Biology, UBC University Examiner Anotida Madzvamuse, Professor, Mathematics, UBC Anotida Madzvamuse University Examiner Marco De Vivo, Associate Director, Computational Sciences, Istituto Italiano di Tecnologia Marco De Vivo External Examiner Additional Supervisory Committee Members: Supervisory Committee Member Additional Supervisory Committee Members: Supervisory Committee Member Additional Supervisory Committee Members: Nathan Lack, Assistant Professor, Urologic Sciences, UBC Supervisory Committee Member Supervisory Committee Member Nada Lallous, Assistant Professor, Urologic Sciences, UBC Supervisory Committee Member iii Abstract In the realm of the development of cancer therapeutics, a significant portion of the human proteome, including over 1600 transcription factors (TFs), is classified as "undruggable". These proteins, often being critical drivers in various cancers, presen…
has type: Thesis/Dissertation
date issued: 2024-11
is shown at: 10.14288/1.0445334
language: eng
degree discipline: Bioinformatics
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Cherkasov, Artem
contributor: Dong, Xuesen
type: Text
identifier URI: http://hdl.handle.net/2429/89202