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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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first_indexed 2021-10-11T15:28:56Z
last_indexed 2021-10-13T03:23:39Z
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2021-10-12T12:10:07.2723925</datestamp><bib-version>v2</bib-version><id>58297</id><entry>2021-10-11</entry><title>Contributions to mathematical pharmacology: new receptor theory with dimeric receptor models</title><swanseaauthors><author><sid>2c93cc32fc33b247636f2a146a33e473</sid><firstname>CARLA</firstname><surname>WHITE</surname><name>CARLA WHITE</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2021-10-11</date><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 a&#xFB00;ects the binding of a ligand to the other protomer. The e&#xFB00;ects of cooperativity on binding dynamics are a primary point of interest.The &#xFB01;rst 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 di&#xFB00;er-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 di&#xFB00;erential equations is investigated using numerical computations and perturbation methods. We see an excellent &#xFB01;t to published data, validating the model.The utility of our models in parameter estimation is explored theoretically using structural identi&#xFB01;ability analysis. This determines which parameters can be theoretically estimated from &#xFB01;tting. This analysis is valuable but often overlooked when &#xFB01;tting to ligand-receptor interaction models. We explore the identi&#xFB01;ability of some canonical lig-and binding models, and our dimer binding models, providing a tutorial and results to contribute to the receptor theory toolbox.</abstract><type>E-Thesis</type><journal/><volume/><journalNumber/><paginationStart/><paginationEnd/><publisher/><placeOfPublication>Swansea</placeOfPublication><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic/><keywords>Mathematics, Pharmacology, Receptor theory, Dimers</keywords><publishedDay>11</publishedDay><publishedMonth>10</publishedMonth><publishedYear>2021</publishedYear><publishedDate>2021-10-11</publishedDate><doi>10.23889/SUthesis.58297</doi><url/><notes>A selection of third party content is redacted or is partially redacted from this thesis due to copyright restrictions.</notes><college>COLLEGE NANME</college><CollegeCode>COLLEGE CODE</CollegeCode><institution>Swansea University</institution><supervisor>Powathil, Gibin ; Kanamarlapudi, Venkateswarlu</supervisor><degreelevel>Doctoral</degreelevel><degreename>Ph.D</degreename><degreesponsorsfunders>Swansea University/ESPRC</degreesponsorsfunders><apcterm/><lastEdited>2021-10-12T12:10:07.2723925</lastEdited><Created>2021-10-11T16:22:28.9373901</Created><path><level id="1">Faculty of Science and Engineering</level><level id="2">School of Mathematics and Computer Science - Mathematics</level></path><authors><author><firstname>CARLA</firstname><surname>WHITE</surname><order>1</order></author></authors><documents><document><filename>58297__21138__53123298ee5442f88f17893862c045f2.pdf</filename><originalFilename>White_Carla_PhD_Thesis_Final_Redacted.pdf</originalFilename><uploaded>2021-10-12T11:58:37.8181463</uploaded><type>Output</type><contentLength>3627144</contentLength><contentType>application/pdf</contentType><version>Redacted version - open access</version><cronfaStatus>true</cronfaStatus><documentNotes>Copyright: The author, Carla White, 2021.</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language></document></documents><OutputDurs/></rfc1807>
spelling 2021-10-12T12:10:07.2723925 v2 58297 2021-10-11 Contributions to mathematical pharmacology: new receptor theory with dimeric receptor models 2c93cc32fc33b247636f2a146a33e473 CARLA WHITE CARLA WHITE true false 2021-10-11 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. E-Thesis Swansea Mathematics, Pharmacology, Receptor theory, Dimers 11 10 2021 2021-10-11 10.23889/SUthesis.58297 A selection of third party content is redacted or is partially redacted from this thesis due to copyright restrictions. COLLEGE NANME COLLEGE CODE Swansea University Powathil, Gibin ; Kanamarlapudi, Venkateswarlu Doctoral Ph.D Swansea University/ESPRC 2021-10-12T12:10:07.2723925 2021-10-11T16:22:28.9373901 Faculty of Science and Engineering School of Mathematics and Computer Science - Mathematics CARLA WHITE 1 58297__21138__53123298ee5442f88f17893862c045f2.pdf White_Carla_PhD_Thesis_Final_Redacted.pdf 2021-10-12T11:58:37.8181463 Output 3627144 application/pdf Redacted version - open access true Copyright: The author, Carla White, 2021. true eng
title Contributions to mathematical pharmacology: new receptor theory with dimeric receptor models
spellingShingle Contributions to mathematical pharmacology: new receptor theory with dimeric receptor models
CARLA WHITE
title_short Contributions to mathematical pharmacology: new receptor theory with dimeric receptor models
title_full Contributions to mathematical pharmacology: new receptor theory with dimeric receptor models
title_fullStr Contributions to mathematical pharmacology: new receptor theory with dimeric receptor models
title_full_unstemmed Contributions to mathematical pharmacology: new receptor theory with dimeric receptor models
title_sort Contributions to mathematical pharmacology: new receptor theory with dimeric receptor models
author_id_str_mv 2c93cc32fc33b247636f2a146a33e473
author_id_fullname_str_mv 2c93cc32fc33b247636f2a146a33e473_***_CARLA WHITE
author CARLA WHITE
author2 CARLA WHITE
format E-Thesis
publishDate 2021
institution Swansea University
doi_str_mv 10.23889/SUthesis.58297
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Mathematics and Computer Science - Mathematics{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Mathematics and Computer Science - Mathematics
document_store_str 1
active_str 0
description 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.
published_date 2021-10-11T04:14:43Z
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score 11.036706

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