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Title: The discovery of small molecule modulators of soluble guanylate cyclase aided by surface plasmon resonance
Author: Mota, F.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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Soluble guanylate cyclase is a multidimeric enzyme that regulates cardiovascular homeostasis and is the receptor for nitric oxide in the brain. The enzyme is the known target for a new agonist drug used for the treatment of pulmonary hypertension. Whilst drug discovery has been successful for the finding of small molecules that activate the enzyme, the currently available inhibitors lack selectivity as they act through oxidation of a heme prosthetic group in the enzyme, which is conserved amongst other hemeproteins. Nonetheless, it has been suggested that inhibition of soluble guanylate cyclase by small molecules could be useful in the treatment of neurological conditions such as Parkinson’s Disease. In this thesis, new activators of soluble guanylate cyclase have been identified by virtual screening, and a new class of inhibitors has been designed and synthesised. The synthetic routes developed are efficient and take advantage of microwave-assisted organic synthesis. The drug-target interaction was characterised using a biophysical technique based on surface plasmon resonance, which allows the detection of label-free binding between small molecules and biological macromolecules. The biophysical assay has been developed using different constructs of soluble guanylate cyclase and validated through binding of the natural ligands ATP and GTP. The instrument and assay design were validated using the well-defined interaction between natriuretic peptides and the extracellular domain of natriuretic peptide type-C. Additional biochemical characterisation of the ligands allowed discrimination between activators and inhibitors. This combination of biophysical and biochemical techniques allowed the identification of the catalytic domain of soluble guanylate cyclase as the target for binding of the new class of synthesised inhibitors and has given insight into the functional groups necessary for activity and binding to the enzyme.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available