An in-silico study of structure-based virtual screening of IDO1 inhibitors as candidate compounds for drug development of IDO1-related diseases

Indoleamine 2, 3 dioxygenase 1 (IDO1) is the rate limiting enzyme of the kynurenine pathway and converts L tryptophan to form N-formylkynurenine. IDO1 and its targeting pathways have been greatly implicated in immunomodulation and tumor development and more recently also neuroinflammation and neurodegeneration. Therefore, within the central nervous system (CNS), IDO1 and the kynurenine pathway play a role in a variety of conditions, including neurodegenerative diseases, neuropsychiatric disorders, and motor neuron diseases. The main mechanism whereby IDO1 and its pathway exert their effects in these conditions is mainly through the generation of excitotoxic metabolic byproducts downstream of the kynurenine pathway, such as quinolinic acid and kynurenic acid, with some being able to easily pass through the blood brain barrier (BBB) and causing microglial activation, astrogliosis, oxidative stress and neuronal apoptosis. Therefore, this study aimed to find inhibitors for IDO1 to potentially be used in further therapeutic studies for different conditions Using AutoDock Vina, docking scores and binding affinities of virtual screening compounds from the drug library on MTiOpenScreen were acquired Compounds with the highest scores and binding affinities were selected and screened from the drug library to perform molecular docking and 2D-plot analysis with IDO1. Further screening was based on Lipinski s rule of five and seganserin was found to be the overall most appropriate inhibitor from the drug library for IDO1 with BBB permeability. Upon further comparison with its related enzymes, namely indoleamine 2,3 dioxygenase 2 (IDO2) and tryptophan 2,3-dioxygenase (TDO) via molecular docking, it was found that binding affinity to seganserin was highest for IDO1.