WOOTTON, Timothy Luke (2023). Synthesis and drug development of small molecule inhibitors of PTP1B. Doctoral, Sheffield Hallam University. [Thesis]
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Wootton_2024_PhD_SynthesisAndDrug.pdf - Accepted Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.
Wootton_2024_PhD_SynthesisAndDrug.pdf - Accepted Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.
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Abstract
PTP1B (Protein tyrosine phosphatase 1B) is a member of the PTP (Protein tyrosine
phosphatase) family of proteins and has previously been identified as a potential
therapeutic target for numerous high-profile disease states, including obesity, type II
diabetes, Alzheimer’s disease and certain cancers including breast cancer. This work
focuses on a means of treatment of metabolic syndrome (obesity, type II diabetes, and
hypertension), by synthesising potential specific small molecule inhibitors of PTP1B that
are impermeable to the blood brain barrier (BBB).
Herein, druggable target sites of PTP1B were investigated computationally, to assist in
the identification of possible PTP1B inhibitors, for subsequent synthesis and testing. This
initially entailed the virtual docking of databases of commercially available compounds,
downloaded from ZINC. The main database used, contained over 870,000,000 ‘drug-like’
compounds as defined by Lipinski’s rule of 5, which resulted in 1822 computational
active site hits. The process of identifying a potential hit was comprised of two stages.
Initially the software used (CrossMiner) classified a molecule as a hit if a Tanimoto ratio
score of ≥ 0.7 was obtained. These initial hits then underwent visual scrutiny by which
any of these ‘hits’ that predominately resided outside of the active site pocket or had
motifs located within the protein were discounted and not considered true hits. The
remaining computational hits were then plotted in pharmaceutically relevant chemical
space, and molecules of interest were selected for further investigation based upon
chemical space location, physiochemical properties, binding mode and ease of synthesis.
This computational work led to an initial compound library of benzodioxanes being
synthesised and tested. The main driving force behind the functionalisation and
modification of the initial hit compound was the ease of synthetic conversion in addition
to desirable changes from computational docking studies.
The potential synthesised inhibitors were then tested for PTP activity against PTP1B and
TCPTP via a yeast-based inhibitory assay where the growth rate of the co-transformed
yeast cells correlates to PTP inhibitor activity. For BBB permeability assessment, a
commercially available kit was utilised, that used a synthetic BBB mimic membrane.
Future work aims to develop the most promising hit into a potential lead compound, thus
contributing to a possible future treatment for the comorbidities of obesity.
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