Dıscovery of New Indoleamıne 2,3-Dıoxygenase 1 (Ido1) Inhıbıtors Through Vırtual Screenıng

Abstract

Cancer, a leading global cause of deaths, utilizes mechanisms and pathways to evade the immune system, one of which is the kynurenine (Kyn) pathway, responsible for degrading amino acid L-tryptophan (Trp). Overexpression of indolamine 2,3-dioxygenase 1 (IDO1), the rate-limiting enzyme of Kyn pathway, in certain cancers makes it a target of interest. In this study, virtual screening was conducted to discover new apo-IDO1 small molecule inhibitors. In the virtual screening process, encompassing both ligand-based and structure-based approaches, three compounds were successfully identified from a commercial library of 555,557 compounds. The library compounds underwent an initial filtering based on drug-likeness parameters to remove those with potentially undesired pharmacokinetic attributes and reactive functional groups. The refined library then underwent parallel ligand-based virtual screening, employing both shape similarity and pharmacophore modeling screening with the involvement of five different known apo-IDO1 inhibitors. The screened library was subsequently docked to the selcted cystallographic human apo-IDO1 structure (PDB ID: 6wjy), which exhibited the best validation results, utilizing standard and then extra precision modes. The top 500 compounds with their three best poses were selected to calculate their MM-GBSA free binding energy (ΔG) values. Fingerprint similarity analysis was performed and similar entities were removed to ensure structural diversity for the selected hits. Among the top scoring 10 compounds regarding MM-GBSA ΔG values, three hits namely STOCK2S-34127, STOCK3S-69016, and STOCK2S-94986, were better than the reference inhibitor. In MD simulations, apo-IDO1 complexes of these hits displayed favorable outcomes, regarding structural conformation and stability, residue fluctuations, compactness, salt bridge formations, and binding free energy. Lastly, the three hits were predicted to show low oral toxicity, moderate toxicity to Daphnia magna, low bioaccumulation in aquatic environments, and be inactive in both nuclear receptor signaling and stress response pathways of toxicity. As a result, STOCK2S-34127, STOCK3S-69016, STOCK2S-94986 were predicted as potent, selective, and safe apo-IDO1 inhibitors, which need to be confirmed via in vitro and in vivo assays.