7AH4

Crystal structure of indoleamine 2,3-dioxygenase 1 (IDO1) in complex with ferric heme and MMG-0363

Summary for 7AH4

• Entry DOI: 10.2210/pdb7ah4/pdb
• Related: 6R63 7AH5 7AH6
• Descriptor: Indoleamine 2,3-dioxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, 4-chloranyl-2-(2~{H}-1,2,3-triazol-4-yl)aniline, ... (4 entities in total)
• Functional Keywords: oxidoreductase, dioxygenase, heme-containing enzyme, structure-based drug design, ido1 inhibitor, triazole, small-molecule inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 97020.46

Authors

Roehrig, U.F.,Reynaud, A.,Pojer, F.,Michielin, O.,Zoete, V. (deposition date: 2020-09-24, release date: 2021-02-17, Last modification date: 2024-11-06)

Primary citation

Rohrig, U.F.,Majjigapu, S.R.,Reynaud, A.,Pojer, F.,Dilek, N.,Reichenbach, P.,Ascencao, K.,Irving, M.,Coukos, G.,Vogel, P.,Michielin, O.,Zoete, V.
Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.
J.Med.Chem., 64:2205-2227, 2021

PubMed Abstract: The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use in anti-cancer immunotherapy. Lead optimization of direct heme iron-binding inhibitors has proven difficult due to the remarkable selectivity and sensitivity of the heme-ligand interactions. Here, we present experimental data for a set of closely related small azole compounds with more than 4 orders of magnitude differences in their inhibitory activities, ranging from millimolar to nanomolar levels. We investigate and rationalize their activities based on structural data, molecular dynamics simulations, and density functional theory calculations. Our results not only expand the presently known four confirmed chemotypes of sub-micromolar heme binding IDO1 inhibitors by two additional scaffolds but also provide a model to predict the activities of novel scaffolds.

PubMed: 33557523
DOI: 10.1021/acs.jmedchem.0c01968

Experimental method

X-RAY DIFFRACTION (2.401 Å)