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Contributions to mathematical pharmacology: new receptor theory with dimeric receptor models / CARLA WHITE

Swansea University Author: CARLA, WHITE

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DOI (Published version): 10.23889/SUthesis.58297

Abstract

Classical receptor theory is largely built on assumptions of monomeric receptors. In this thesis, we contribute to receptor theory by considering the now widely accepted cases of dimeric receptors. The implications of dimerisation for drug discovery and therapeutics remain unclear. Therefore, a theo...

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Published: Swansea 2021
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Powathil, Gibin ; Kanamarlapudi, Venkateswarlu
URI: https://cronfa.swan.ac.uk/Record/cronfa58297
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Abstract: Classical receptor theory is largely built on assumptions of monomeric receptors. In this thesis, we contribute to receptor theory by considering the now widely accepted cases of dimeric receptors. The implications of dimerisation for drug discovery and therapeutics remain unclear. Therefore, a theoretical consideration of ligand binding and signalling via receptor dimers is warranted. Here, we develop mathematical models for ligand bind-ing at dimerised and dimerising receptors. A key factor in developing these theoretical models is cooperativity across the dimer, whereby binding of a ligand to one protomer affects the binding of a ligand to the other protomer. The effects of cooperativity on binding dynamics are a primary point of interest.The first models we present focus on G protein-coupled receptors, where we assume that all receptors are pre-dimerised. Ligand binding models give linear systems of differ-ential equations which we use to analyse time course behaviours. At equilibrium, these models may exhibit multi-phasic log dose response curves, critically depending on co-operativity factors. When considering receptor activation, we see dose response curves that are indicative of non-standard ligand-receptor interactions, giving a quantitative and qualitative platform for analysing and interpreting data when dimers are suspected. A ligand induced model for vascular endothelial growth factor receptors is developed, whereby receptors exist constitutively as monomers and dimerise in response to ligand binding. The resulting nonlinear system of differential equations is investigated using numerical computations and perturbation methods. We see an excellent fit to published data, validating the model.The utility of our models in parameter estimation is explored theoretically using structural identifiability analysis. This determines which parameters can be theoretically estimated from fitting. This analysis is valuable but often overlooked when fitting to ligand-receptor interaction models. We explore the identifiability of some canonical lig-and binding models, and our dimer binding models, providing a tutorial and results to contribute to the receptor theory toolbox.
Item Description: A selection of third party content is redacted or is partially redacted from this thesis due to copyright restrictions.
Keywords: Mathematics, Pharmacology, Receptor theory, Dimers
College: College of Science