Synthesis and drug development of small molecule inhibitors of PTP1B

WOOTTON, Timothy Luke (2023). Synthesis and drug development of small molecule inhibitors of PTP1B. Doctoral, Sheffield Hallam University.

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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.

Item Type:	Thesis (Doctoral)
Contributors:	Thesis advisor - Allwood, Daniel [0000-0002-3735-3198] (Affiliation: Sheffield Hallam University) Thesis advisor - Aberdein, Nicola [0000-0002-6147-4221] (Affiliation: Sheffield Hallam University) Thesis advisor - Princivalle, Alessandra [0000-0001-5375-0604] (Affiliation: Sheffield Hallam University)
Additional Information:	Director of studies: Dr. Daniel M. Allwood / Supervisors: Dr. Nicola Aberdein and Dr. Alessandra Princivalle
Research Institute, Centre or Group - Does NOT include content added after October 2018:	Sheffield Hallam Doctoral Theses
Identification Number:	https://doi.org/10.7190/shu-thesis-00609
Depositing User:	Colin Knott
Date Deposited:	21 May 2024 14:57
Last Modified:	22 May 2024 02:02
URI:	https://shura.shu.ac.uk/id/eprint/33738

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