Indoleamine 2,3-dioxygenase 1: mapping the active site and discovery of novel inhibitors
thesisposted on 2022-03-28, 13:30 authored 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.