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Indoleamine 2,3-dioxygenase 1: mapping the active site and discovery of novel inhibitors

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thesis
posted on 28.03.2022, 13:30 by Jason R. Smith
Indoleamine 2,3‐dioxygenase‐1 (IDO‐1) is a heme‐containing enzyme that catalyses the initial step in the major pathway of L‐tryptophan catabolism; the kynurenine pathway. A large body of evidence has been accumulating for its immunosuppressive and tumoural escape roles and its applicability as a therapeutic target. Of particular interest is the possibility that IDO‐1 inhibition may arrest, and sometimes revert, tumour growth. To date only two molecules have achieved phase 1 clinical testing, therefore, there exists a continuing need for the development of new IDO‐1 inhibitors as therapeutic leads. This project seeks to combine experimental and computational approaches to firstly, understand the process of ligand binding to IDO‐1, and secondly, screen for new and unique inhibitors of IDO‐1. Progress has been made towards mapping the ligand binding interactions of IDO‐1 through photoaffinity labelling. This involved synthesis of substrate analogues capable of forming covalent linkages to the enzyme in a controlled manner. Analysis of these experiments through mass spectrometric techniques was then used to identify sites of attachment. Parallel to this, high throughput in silico screening (utilising multiple pharmacophores and an innovative ‘What‐If’ docking technique) was performed, and identified four novel inhibitors with a unique esterimidamide structural element. These models suggest that these molecules show great promise for development of potent and specific IDO‐1 inhibitors.

History

Table of Contents

1. Introduction -- 2. Selection and synthesis of photoaffinity labels -- 3. Photoaffinity labelling of rhIDO-1 by azidotryptophans -- 4. IDO-1 and small molecule inhibitors -- 5. Experiments to further understand the interactions of selected scaffolds with rhIDO-1 --6. In silico screening of new IDO-1 inhibitors -- 7. Conclusions and future directions.

Notes

Includes bibliographical references A thesis submitted in the partial fulfillment of the requirements for the award of the degree of Master of Philosophy.

Awarding Institution

Macquarie University

Degree Type

Thesis masters research

Degree

Thesis (MPhil), Macquarie University, Faculty of Science, Department of Chemistry and Biomolecular Sciences

Department, Centre or School

Department of Chemistry and Biomolecular Sciences

Year of Award

2012

Principal Supervisor

Joanne F. Jamie

Additional Supervisor 1

Robert D. Willows

Rights

Copyright disclaimer: http://mq.edu.au/library/copyright

Language

English

Extent

1 online resource (x, 203 pages) illustrations

Former Identifiers

mq:53858 http://hdl.handle.net/1959.14/1138188