Date of Award

5-12-2024

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

James Hougland

Keywords

ghrelin;GOAT

Subject Categories

Chemistry | Physical Sciences and Mathematics

Abstract

Ghrelin is a 28-amino acid peptide hormone that has wide-ranging physiological effects, including on metabolism, adipogenesis, insulin regulation, and addiction. Ghrelin offers an intriguing option for treatment of pathophysiologies related to these effects, as it requires a unique post-translational octanoyl modification to bind and activate its cognate receptor, growth hormone secretagogue 1a (GHSR). The enzyme responsible for this modification, ghrelin O-acyltransferase (GOAT) therefore offers the ability to modulate ghrelin signaling through inhibition of the maturation pathway. Due to a lack of structural or mechanistic information about GOAT, pharmaceutical development of molecules capable of GOAT inhibition has been desired, but few molecules have been reported. To aid in the development of small-molecule inhibitors capable of GOAT inhibition, we have altered an existing GOAT activity assay for high-throughput screening capabilities. Utilization of this modified assay in conjunction with computational modeling has led to the development of novel molecules capable of GOAT inhibition. In addition, new classes of GOAT inhibitors have led to insights on the potential catalytic mechanism of GOAT.

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Open Access

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Chemistry Commons

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