Structure and Plasticity of Indoleamine 2,3-Dioxygenase 1 (IDO1)

Abstract

Since the discovery of the implication of indoleamine 2,3-dioxygenase 1 (IDO1) in tumoral immune resistance in 2003, the search for inhibitors has been intensely pursued both in academia and in pharmaceutical companies, supported by the publication of the first crystal structure of IDO1 in 2006. More recently, it has become clear that IDO1 is an important player in various biological pathways and diseases ranging from neurodegenerative diseases to infection and autoimmunity. Its inhibition may lead to clinical benefit in different therapeutic settings. At present, over 50 experimental structures of IDO1 in complex with different ligands are available in the Protein Data Bank. Our analysis of this wealth of structural data sheds new light on several open issues regarding IDO1’s structure and function.

Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls

“…In this framework, the availability of numerous IDO1 crystallographic studies has prompted the structure-based design as a method of choice to identify and optimize inhibitors bearing different chemical scaffolds and mechanisms of binding to the enzyme [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. These works have unveiled a conserved fold of the IDO1 primary sequence, which is composed of a large catalytic domain and a small non-catalytic domain ( Figure 3 a).…”

Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors

“…Based on the ongoing interest for IDO1 inhibitors capable of modulating these different pathways and processes selectively, a multitude of small-molecule IDO1 inhibitors have been described 19 , 20 , and more than 60 crystal structures of IDO1 have been deposited in the protein data bank (PDB) 21 . These structures with a large diversity of bound cofactors and ligands, including the clinical-stage IDO1 inhibitors epacadostat ( 1 , INCB024360, Figure 1 A) 23 , navoximod ( 2 , NLG-919/GDC919) 24 , EOS200271 ( 3 ) 25 , and linrodostat ( 4 , BMS-986205) 26 , yield a wealth of information for inhibitor design 27 .…”

“…Lead optimisation of haem-iron binding type ii and type iii inhibitors has proven difficult due to the selectivity and sensitivity of the haem–ligand interactions to changes in the electronic structure of the ligand 28 and due to the small size of the distal haem pocket (pocket A) 29 , crucial for inhibitor activity. The IDO1 active site further comprises Pocket B, which extends from pocket A towards the entrance of the active site ( Figure 1B,C ), and whose size and shape are determined by the conformation of the flexible JK-loop 27 . Although its influence on inhibitor affinity is less pronounced than pocket A, it is of interest for modulation of other compound properties such as specificity, absorption, distribution, metabolism and excretion (ADME), and pharmacokinetics/pharmacodynamics (PK/PD).…”

“…Epacadostat ( 1 ) binds to the haem iron through an unusual high-affinity hydroxyamidine scaffold, which was discovered by Incyte 23 , 30 and has later been exploited by other groups 31–38 . Due to its unique tilted iron-binding conformation, it provides a straightforward access to pocket B and allowed the development of numerous nanomolar IDO1 inhibitors with a high selectivity over TDO 27 . Except for the hydroxyamidines, almost all nanomolar haem-binding IDO1 inhibitors are based on a haem-binding free or fused azole scaffold.…”

“…Analysing the active site structure of IDO1 and the chemical structures of other known IDO1 inhibitors, it would be natural to extend the compounds from pocket A in the haem distal site to pocket B towards the entrance of the active site ( Figure 1D ). However, azole ligands are not optimally suited to be extended to pocket B due to their preferred orientation, and this extension often leads to a dramatic decrease in activity for many compounds 27 . Here, we resolve one new X-ray structure of a previously reported triazole extending to pocket B ( 13 , MMG-0472), which validates our docking predictions.…”