Computational study on new natural compound inhibitors of indoleamine 2,3-dioxygenase 1

Abstract

Indoleamine 2,3-Dioxygenase (IDO), is a speed limiting enzyme that catalyzes the decomposition and metabolism of Tryptophan along Tryptophan-IDO-Kynurenine pathway [1]. Tryptophan is a necessary amino acid for activating cell growth and metabolism. Additionally, the insufficiency of Tryptophan can lead to immune system dysfunction. Raising the level of Indoleamine 2,3-Dioxygenase protein can promote stagnation and apoptosis of effector T cells [2].In contrast, the decline in the number of effect T cells naturally protects cancer cells from attack. Therefore, Indoleamine 2,3-Dioxygenase is a potential target for tumour immunotherapy, such as melanoma, ovarian cancer, lung cancer, leukaemia, and so on, especially in solid tumours [3]. In the study, we have done sets of virtual screening aided by computer techniques in order to find potentially effective inhibitors of Indoleamine 2,3-Dioxygenase. Firstly, screening based on structure was carried out by Libdock. Then, ADME (adsorption, distribution, metabolism, excretion) and toxicity prediction were also analyzed. Molecular docking and 3D-QSAR pharmacophore generation were used to study the mechanism of these compounds and Indoleamine 2,3-Dioxygenase's binding. A molecular dynamic analysis was carried out to assess if these potential compound's binding is stable enough. According to the results of the analysis above, two potential compounds (ZINC000012495022 and ZINC000003791817) from the ZINC database were discovered to interact with Indoleamine 2,3-Dioxygenase with appropriate energy and proved to be none toxic. The study offered valuable information of Indoleamine 2,3-Dioxygenase inhibitor-based drug discovery in cancer therapy by increasing the activity of T cells and releasing immunity suppression [4, 5].

Keywords: IDO (Indoleamine 2,3-Dioxygenase); inhibitor; tryptophan; virtual screening.

Figure 1

The structures of ABZI and novel compounds selected from virtual screening by chemdraw.

Figure 2

(A) ZINC000012495022-IDO complex. Schematic drawing of interactions between ligands and IDO, the surface of binding area were added, blue represented positive charge, red represented negative charge, and ligands were shown in sticks, the structure around the ligand-receptor junction were shown in thinner sticks. (B) ZINC000003791817-IDO complex. Schematic drawing of interactions between ligands and IDO, the surface of binding area were added, blue represented positive charge, red represented negative charge, and ligands were shown in sticks, the structure around the ligand-receptor junction were shown in thinner sticks. (C) Epacadostat-IDO complex. Schematic drawing of interactions between ligands and IDO, the surface of binding area were added, blue represented positive charge, red represented negative charge, and ligands were shown in sticks, the structure around the ligand-receptor junction were shown in thinner sticks.

Figure 3

The inter-molecular interaction of the predicted binding modes of (A) ZINC000003791817 to IDO; (B) ZINC000012495022 to IDO, (C) Epacadostat to IDO.

Figure 4

Pharmacophore predictions using 3D-QSAR. (A) ZINC000012495022: Green represents hydrogen acceptor, and blue represents hydrophobic center and dark blue represents Ionizable negative. (B) ZINC000003791817: Green represents hydrogen acceptor, blue represents hydrophobic center, purple represents hydrogen donor, and dark blue represents Ionizable negative.

Figure 5

Results of molecular dynamics simulation of three complexes. (A) Potential Energy; (B) Average backbone RMSD.

Figure 6

Animal experiments to against tumor activity. Tumor-bearing mice were treated with compound 1,2 at dosage of 10 mg/kg, respectively. (A) Mean tumor volumes. (B) Survival percentage of Mice. (C) Tumor weights on 20^th day. Data were represented as Mean ± SEM, p<0.05 and p<0.01.

Figure 7

The molecular structure of IDO. Initial molecular structure was shown in (A) the surface of binding area were added in (B) and the complex structure of IDO with Epacadostat in (C) blue represented positive charge, red represented negative charge and green was used to label the cartoon.