Discovery of novel IDO1 inhibitors via structure-based virtual screening and biological assays |
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Authors: | Ge Huizhen Mao Longfei Zhao Jie Wang Yuwei Shi Danfeng Yang Xing Wang Xiaorui Liu Huanxiang Yao Xiaojun |
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Institution: | 1.School of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China ;2.School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, 453007, China ;3.State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China ;4.School of Pharmacy, Lanzhou University, Lanzhou, 730000, China ; |
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Abstract: | Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the first and rate-limiting step in catabolism of tryptophan via the kynurenine pathway, which plays a pivotal role in the proliferation and differentiation of T cells. IDO1 has been proven to be an attractive target for many diseases, such as breast cancer, lung cancer, colon cancer, prostate cancer, etc. In this study, docking-based virtual screening and bioassays were conducted to identify novel inhibitors of IDO1. The cellular assay demonstrated that 24 compounds exhibited potent inhibitory activity against IDO1 at micromolar level, including 8 compounds with IC50 values below 10 μM and the most potent one (compound 1) with IC50 of 1.18?±?0.04 μM. Further lead optimization based on similarity searching strategy led to the discovery of compound 28 as an excellent inhibitor with IC50 of 0.27?±?0.02 μM. Then, the structure–activity relationship of compounds 1, 2, 8 and 14 analogues is discussed. The interaction modes of two compounds against IDO1 were further explored through a Python Based Metal Center Parameter Builder (MCPB.py) molecular dynamics simulation, binding free energy calculation and electrostatic potential analysis. The novel IDO1 inhibitors of compound 1 and its analogues could be considered as promising scaffold for further development of IDO1 inhibitors. |
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