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Department of Pharmacology

Hilšer, A

G protein-coupled receptors (GPCRs) are a big family of membrane receptors encoded by more than 800 genes in humans. The vast number and diversity of GPCRs enables them to interact with an equally great number of ligands enabling them to regulate many physiological functions such as senses, metabolism, neurotransmission or cell growth. Given GPCRs’ involvement in the regulation of many physiological functions, it then comes as no surprise that their malfunction often leads to pathological states such as cancer, diabetes mellitus, inflammation or central nervous system disorders. This makes GPCRs the focus of drug discovery with roughly 34% of all FDA (Food and drug administration) approved drugs targeting them. This thesis presents the drug discovery at adenosine receptors, class A GPCRs, and gastric inhibitory polypeptide receptor (GIPR), a class B GPCR.
Given the possible therapeutic effects of modulating GIPR signalling pathway in diabetes and obesity, the primary objective of this thesis was to discover and improve GIPR allosteric modulators using both in silico and in vitro techniques. This resulted in successful identification of potent and selective GIPR negative allosteric modulators like compound C25, while also investigating the bias of the compounds at different pathways and their selectivity. Combinational approach of in silico blind docking and in vitro mutagenesis was then used to successfully identify the GIPR allosteric binding site of the compounds located around at the top of transmembrane domain 2/3 and extracellular loop 1.
The second part of this thesis is then focused on drug discovery at adenosine receptors with the aim of developing more selective and more potent compounds. Firstly, compounds were screened for more potent adenosine 1 agonists that would retain or improve upon BnOCPA compound, which is a powerful analgesic lacking the common side effects. This was successfully achieved and some really potent and selective adenosine 1 agonists like compound 27 were identified. Secondly, potent adenosine 1 and adenosine 3 antagonists were discovered, and their potency, selectivity and binding were measured. This led to the identification of several potent dual adenosine 1 and 3 antagonists like compounds A17 and A47, which hold potential in the treatment of asthma, lowering intraocular pressure or in several central nervous system disorders.
Ultimately, these findings show how a combinational approach of in silico and in vitro pharmacology can be successfully used to identify new small molecule GPCR allosteric modulators and identify new potent adenosine receptor agonists and antagonists with potential therapeutic benefits.

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29 April 2023
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Theses / dissertations
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University of Cambridge
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Ladds, G