Skip to main content

Advertisement

SpringerLink
Log in

Discovery of novel IDO1 inhibitors via structure-based virtual screening and biological assays

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Cheong JE, Ekkati A, Sun L (2018) A patent review of IDO1 inhibitors for cancer. Expert Opin Ther Pat 28(4):317–330. https://doi.org/10.1080/13543776.2018.1441290

    Article  CAS  PubMed  Google Scholar 

  2. Comai S, Bertazzo A, Brughera M, Crotti S (2020) Tryptophan in health and disease. Adv Clin Chem 95:165–218. https://doi.org/10.1016/bs.acc.2019.08.005

    Article  CAS  PubMed  Google Scholar 

  3. Le Floc’h N, Otten W, Merlot E (2011) Tryptophan metabolism, from nutrition to potential therapeutic applications. Amino Acids 41(5):1195–1205. https://doi.org/10.1007/s00726-010-0752-7

    Article  CAS  PubMed  Google Scholar 

  4. Takikawa O (2005) Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated L-tryptophan metabolism. Biochem Biophys Res Commun 338(1):12–19. https://doi.org/10.1016/j.bbrc.2005.09.032

    Article  CAS  PubMed  Google Scholar 

  5. Yang R, Chen Y, Pan L, Yang Y, Zheng Q, Hu Y, Wang Y, Zhang L, Sun Y, Li Z, Meng X (2018) Design, synthesis and structure-activity relationship study of novel naphthoindolizine and indolizinoquinoline-5,12-dione derivatives as IDO1 inhibitors. Bioorg Med Chem 26(17):4886–4897. https://doi.org/10.1016/j.bmc.2018.08.028

    Article  CAS  PubMed  Google Scholar 

  6. Tojo S, Kohno T, Tanaka T, Kamioka S, Ota Y, Ishii T, Kamimoto K, Asano S, Isobe Y (2014) Crystal structures and structure-activity relationships of imidazothiazole derivatives as IDO1 inhibitors. ACS Med Chem Lett 5(10):1119–1123. https://doi.org/10.1021/ml500247w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yan D, Lin YW, Tan X (2017) Heme-containing enzymes and inhibitors for tryptophan metabolism. Metallomics 9(9):1230–1240

    Article  CAS  PubMed  Google Scholar 

  8. Coluccia A, Passacantilli S, Famiglini V, Sabatino M, Patsilinakos A, Ragno R, Mazzoccoli C, Sisinni L, Okuno A, Takikawa O, Silvestri R, La Regina G (2016) New Inhibitors of Indoleamine 2,3-Dioxygenase 1: Molecular Modeling Studies, Synthesis, and Biological Evaluation. J Med Chem 59(21):9760–9773. https://doi.org/10.1021/acs.jmedchem.6b00718

    Article  CAS  PubMed  Google Scholar 

  9. Shiokawa Z, Kashiwabara E, Yoshidome D, Fukase K, Inuki S, Fujimoto Y (2016) Discovery of a novel scaffold as an indoleamine 2,3-Dioxygenase 1 (IDO1) inhibitor based on the pyrrolopiperazinone alkaloid. Longamide B ChemMedChem 11(24):2682–2689. https://doi.org/10.1002/cmdc.201600446

    Article  CAS  PubMed  Google Scholar 

  10. Brochez L, Chevolet I, Kruse V (2017) The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. Eur J Cancer 76:167–182. https://doi.org/10.1016/j.ejca.2017.01.011

    Article  CAS  PubMed  Google Scholar 

  11. Brant MG, Goodwin-Tindall J, Stover KR, Stafford PM, Wu F, Meek AR, Schiavini P, Wohnig S, Weaver DF (2018) Identification of potent indoleamine 2,3-Dioxygenase 1 (IDO1) inhibitors based on a phenylimidazole scaffold. ACS Med Chem Lett 9(2):131–136. https://doi.org/10.1021/acsmedchemlett.7b00488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fang K, Dong G, Li Y, He S, Wu Y, Wu S, Wang W, Sheng C (2018) Discovery of novel indoleamine 2,3-Dioxygenase 1 (IDO1) and histone deacetylase (HDAC) dual inhibitors. ACS Med Chem Lett 9(4):312–317. https://doi.org/10.1021/acsmedchemlett.7b00487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hornyak L, Dobos N, Koncz G, Karanyi Z, Pall D, Szabo Z, Halmos G, Szekvolgyi L (2018) The role of indoleamine-2,3-Dioxygenase in cancer development, diagnostics, and therapy. Front Immunol 9:151. https://doi.org/10.3389/fimmu.2018.00151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fang K, Dong G, Wang H, He S, Wu S, Wang W, Sheng C (2018) Improving the potency of cancer immunotherapy by dual targeting of IDO1 and DNA. Chem Med Chem 13(1):30–36. https://doi.org/10.1002/cmdc.201700666

    Article  CAS  PubMed  Google Scholar 

  15. Hong R, Zhou Y, Tian X, Wang L, Wu X (2018) Selective inhibition of IDO1, D-1-methyl-tryptophan (D-1MT), effectively increased EpCAM/CD3-bispecific BiTE antibody MT110 efficacy against IDO1(hi)breast cancer via enhancing immune cells activity. Int Immunopharmacol 54:118–124. https://doi.org/10.1016/j.intimp.2017.10.008

    Article  CAS  PubMed  Google Scholar 

  16. Volaric A, Gentzler R, Hall R, Mehaffey JH, Stelow EB, Bullock TN, Martin LW, Mills AM (2018) Indoleamine-2,3-Dioxygenase in non-small cell lung cancer: a targetable mechanism of immune resistance frequently coexpressed with PD-L1. Am J Surg Pathol 42(9):1216–1223. https://doi.org/10.1097/PAS.0000000000001099

    Article  PubMed  Google Scholar 

  17. Lee SJ, Jun S-Y, Lee IH, Kang BW, Park SY, Kim HJ, Park JS, Choi G-S, Yoon G, Kim JG (2018) CD274, LAG3, and IDO1 expressions in tumor-infiltrating immune cells as prognostic biomarker for patients with MSI-high colon cancer. J Cancer Res Clin Oncol 144(6):1005–1014. https://doi.org/10.1007/s00432-018-2620-x

    Article  CAS  PubMed  Google Scholar 

  18. Chen IC, Lee KH, Hsu YH, Wang WR, Chen CM, Cheng YW (2016) Expression pattern and clinicopathological relevance of the indoleamine 2,3-Dioxygenase 1/Tryptophan 2,3-Dioxygenase protein in colorectal cancer. Dis Markers 2016:8169724. https://doi.org/10.1155/2016/8169724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kolijn K, Verhoef EI, Smid M, Böttcher R, Jenster GW, Debets R, van Leenders GJLH (2018) Epithelial-mesenchymal transition in human prostate cancer demonstrates enhanced immune evasion marked by IDO1 expression. Cancer Res 78(16):4671–4679. https://doi.org/10.1158/0008-5472.can-17-3752

    Article  CAS  PubMed  Google Scholar 

  20. Zhang W, Zhang J, Zhang Z, Guo Y, Wu Y, Wang R, Wang L, Mao S, Yao X (2018) Overexpression of indoleamine 2,3-Dioxygenase 1 promotes epithelial-mesenchymal transition by activation of the IL-6/STAT3/PD-L1 pathway in bladder cancer. Transl Oncol 12(3):485–492. https://doi.org/10.1016/j.tranon.2018.11.012

    Article  PubMed  PubMed Central  Google Scholar 

  21. Brody JR, Costantino CL, Berger AC, Sato T, Lisanti MP, Yeo CJ, Emmons RV, Witkiewicz AK (2009) Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival. Cell Cycle 8(12):1930–1934. https://doi.org/10.4161/cc.8.12.8745

    Article  CAS  PubMed  Google Scholar 

  22. Le Naour J, Galluzzi L, Zitvogel L, Kroemer G, Vacchelli E (2020) Trial watch: IDO inhibitors in cancer therapy. Oncoimmunology 9(1):1777625. https://doi.org/10.1080/2162402X.2020.1777625

    Article  PubMed  PubMed Central  Google Scholar 

  23. Jiang T, Sun Y (2015) Research progress of indoleamine 2,3-dioxygenase inhibitors. Future Med Chem 7(2):185–201. https://doi.org/10.4155/fmc.14.151

    Article  CAS  PubMed  Google Scholar 

  24. Komiya T, Huang CH (2018) Updates in the clinical development of epacadostat and other indoleamine 2,3-Dioxygenase 1 inhibitors (IDO1) for human cancers. Front Oncol 8:423. https://doi.org/10.3389/fonc.2018.00423

    Article  PubMed  PubMed Central  Google Scholar 

  25. Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M, Mellor AL, Prendergast GC, Munn DH (2007) Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res 67(2):792–801. https://doi.org/10.1158/0008-5472.CAN-06-2925

    Article  CAS  PubMed  Google Scholar 

  26. Yue EW, Douty B, Wayland B, Bower M, Liu X, Leffet L, Wang Q, Bowman KJ, Hansbury MJ, Liu C, Wei M, Li Y, Wynn R, Burn TC, Koblish HK, Fridman JS, Metcalf B, Scherle PA, Combs AP (2009) Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model. J Med Chem 52(23):7364–7367. https://doi.org/10.1021/jm900518f

    Article  CAS  PubMed  Google Scholar 

  27. Yue EW, Sparks R, Polam P, Modi D, Douty B, Wayland B, Glass B, Takvorian A, Glenn J, Zhu W, Bower M, Liu X, Leffet L, Wang Q, Bowman KJ, Hansbury MJ, Wei M, Li Y, Wynn R, Burn TC, Koblish HK, Fridman JS, Emm T, Scherle PA, Metcalf B, Combs AP (2017) INCB24360 (Epacadostat), a Highly Potent and Selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology. ACS Med Chem Lett 8(5):486–491. https://doi.org/10.1021/acsmedchemlett.6b00391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Peng YH, Ueng SH, Tseng CT, Hung MS, Song JS, Wu JS, Liao FY, Fan YS, Wu MH, Hsiao WC, Hsueh CC, Lin SY, Cheng CY, Tu CH, Lee LC, Cheng MF, Shia KS, Shih C, Wu SY (2016) Important Hydrogen Bond Networks in Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Design Revealed by Crystal Structures of Imidazoleisoindole Derivatives with IDO1. J Med Chem 59(1):282–293. https://doi.org/10.1021/acs.jmedchem.5b01390

    Article  CAS  PubMed  Google Scholar 

  29. Nayak-Kapoor A, Hao Z, Sadek R, Dobbins R, Marshall L, Vahanian NN, Jay Ramsey W, Kennedy E, Mautino MR, Link CJ, Lin RS, Royer-Joo S, Liang X, Salphati L, Morrissey KM, Mahrus S, McCall B, Pirzkall A, Munn DH, Janik JE, Khleif SN (2018) Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors. J Immunother Cancer 6(1):61. https://doi.org/10.1186/s40425-018-0351-9

    Article  PubMed  PubMed Central  Google Scholar 

  30. Zhao Y, Wang B, Liu J, Sun P, Liu H (2018) An overview on the methods of determining the activity of indoleamine 2, 3-dioxygenase 1. J Drug Target 27(7):724–731. https://doi.org/10.1080/1061186X.2018.1523416

    Article  PubMed  Google Scholar 

  31. Xu L, Zhang Y, Zheng L, Qiao C, Li Y, Li D, Zhen X, Hou T (2014) Discovery of novel inhibitors targeting the macrophage migration inhibitory factor via structure-based virtual screening and bioassays. J Med Chem 57(9):3737–3745. https://doi.org/10.1021/jm401908w

    Article  CAS  PubMed  Google Scholar 

  32. Shen M, Tian S, Pan P, Sun H, Li D, Li Y, Zhou H, Li C, Lee SM, Hou T (2015) Discovery of novel ROCK1 inhibitors via integrated virtual screening strategy and bioassays. Sci Rep 5:16749. https://doi.org/10.1038/srep16749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang G, Xing J, Wang Y, Wang L, Ye Y, Lu D, Zhao J, Luo X, Zheng M, Yan S (2018) Discovery of novel inhibitors of indoleamine 2,3-Dioxygenase 1 through structure-based virtual screening. Front Pharmacol 9:277. https://doi.org/10.3389/fphar.2018.00277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chong CM, Kou MT, Pan P, Zhou H, Ai N, Li C, Zhong HJ, Leung CH, Hou T, Lee SM (2016) Discovery of a novel ROCK2 inhibitor with anti-migration effects via docking and high-content drug screening. Mol Biosyst 12(9):2713–2721. https://doi.org/10.1039/c6mb00343e

    Article  CAS  PubMed  Google Scholar 

  35. Tian S, Wang X, Li L, Zhang X, Li Y, Zhu F, Hou T, Zhen X (2017) Discovery of novel and selective adenosine A2A receptor antagonists for treating parkinson’s disease through comparative structure-based virtual screening. J Chem Inf Model 57(6):1474–1487. https://doi.org/10.1021/acs.jcim.7b00188

    Article  CAS  PubMed  Google Scholar 

  36. Tomek P, Palmer BD, Flanagan JU, Sun C, Raven EL, Ching LM (2017) Discovery and evaluation of inhibitors to the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1): Probing the active site-inhibitor interactions. Eur J Med Chem 126:983–996. https://doi.org/10.1016/j.ejmech.2016.12.029

    Article  CAS  PubMed  Google Scholar 

  37. Zhong H, Wang Z, Wang X, Liu H, Li D, Liu H, Yao X, Hou T (2019) Importance of a crystalline water network in docking-based virtual screening: a case study of BRD4. Phys Chem Chem Phys 21(45):25276–25289. https://doi.org/10.1039/C9CP04290C

    Article  CAS  PubMed  Google Scholar 

  38. Wang Z, Sun H, Shen C, Hu X, Gao J, Li D, Cao D, Hou T (2020) Combined strategies in structure-based virtual screening. Phys Chem Chem Phys 22(6):3149–3159. https://doi.org/10.1039/c9cp06303j

    Article  CAS  PubMed  Google Scholar 

  39. Zou Y, Wang F, Wang Y, Guo W, Zhang Y, Xu Q, Lai Y (2017) Systematic study of imidazoles inhibiting IDO1 via the integration of molecular mechanics and quantum mechanics calculations. Eur J Med Chem 131:152–170. https://doi.org/10.1016/j.ejmech.2017.03.021

    Article  CAS  PubMed  Google Scholar 

  40. Schrödinger, version 10.1; Schrödinger, LLC: New York (2015).

  41. Kaminski GA, Friesner RA, Tirado-Rives J, Jorgensen WL (2001) Evaluation and reparametrization of the OPLS-AA force field for proteins via comparison with accurate quantum chemical calculations on peptides. J Phys Chem 105(28):6474–6487. https://doi.org/10.1021/jp003919d

    Article  CAS  Google Scholar 

  42. Lipinski CA (2004) Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol 1(4):337–341. https://doi.org/10.1016/j.ddtec.2004.11.007

    Article  CAS  PubMed  Google Scholar 

  43. Fung SP, Wang H, Tomek P, Squire CJ, Flanagan JU, Palmer BD, Bridewell DJ, Tijono SM, Jamie JF, Ching LM (2013) Discovery and characterisation of hydrazines as inhibitors of the immune suppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1). Bioorg Med Chem 21(24):7595–7603. https://doi.org/10.1016/j.bmc.2013.10.037

    Article  CAS  PubMed  Google Scholar 

  44. Richards T, Brin E (2018) Cell based functional assays for IDO1 inhibitor screening and characterization. Oncotarget 9(56):30814–30820. https://doi.org/10.18632/oncotarget.25720

    Article  PubMed  PubMed Central  Google Scholar 

  45. Li P, Merz KM Jr (2016) MCPBpy: a python based metal center parameter builder. J Chem Inf Model 56(4):599–604. https://doi.org/10.1021/acs.jcim.5b00674

    Article  CAS  PubMed  Google Scholar 

  46. Oda A, Yamaotsu N, Hirono S (2005) New AMBER force field parameters of heme iron for cytochrome P450s determined by quantum chemical calculations of simplified models. J Comput Chem 26(8):818–826. https://doi.org/10.1002/jcc.20221

    Article  CAS  PubMed  Google Scholar 

  47. Frisch MJ, Schlegel HB, Scuseria GE, Robb MA, Scalmani G, Barone V, Mennucci B, Petersson GA, Caricato HN, Li X, Hratchian HP, Izmaylov AF, Zheng G, Sonnenberg JL, Hada M, Ehara M, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Nakai H, Vreven T, Montgomery JA, Peralta JE, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Kobayashi R, Normand J, Raghavachari K, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Cammi R, Pomelli C, Ochterski JW, Martin RL, Zakrzewski VG, Voth GA, Salvador P, Dapprich S, Daniels AD, Farkas O, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09. Gaussian Inc, Wallingford

    Google Scholar 

  48. Junmei W, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25(9):1157–1174. https://doi.org/10.1002/jcc.20035

    Article  CAS  Google Scholar 

  49. Maier JA, Martinez C, Kasavajhala K, Wickstrom L, Hauser KE, Simmerling C (2015) ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB. J Chem Theory Comput 11(8):3696–3713. https://doi.org/10.1021/acs.jctc.5b00255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Case DA, Cheatham TE 3rd, Darden T, Gohlke H, Luo R, Merz KM Jr, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) The Amber biomolecular simulation programs. J Comput Chem 26(16):1668–1688. https://doi.org/10.1002/jcc.20290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Xu L, Sun H, Li Y, Wang J, Hou T (2013) Assessing the performance of MM/PBSA and MM/GBSA methods 3 The impact of force fields and ligand charge models. J Phys Chem B 117(28):8408–8421. https://doi.org/10.1021/jp404160y

    Article  CAS  PubMed  Google Scholar 

  52. Sun H, Li Y, Tian S, Xu L, Hou T (2014) Assessing the performance of MM/PBSA and MM/GBSA methods 4 Accuracies of MM/PBSA and MM/GBSA methodologies evaluated by various simulation protocols using PDBbind data set. Phys Chem Chem Phys 16(31):16719–16729. https://doi.org/10.1039/c4cp01388c

    Article  CAS  PubMed  Google Scholar 

  53. Hou T, Wang J, Li Y, Wang W (2011) Assessing the performance of the MM/PBSA and MM/GBSA methods 1 the accuracy of binding free energy calculations based on molecular dynamics simulations. J Chem Inf Model 51(1):69–82. https://doi.org/10.1021/ci100275a

    Article  CAS  PubMed  Google Scholar 

  54. Sun H, Li Y, Shen M, Tian S, Xu L, Pan P, Guan Y, Hou T (2014) Assessing the performance of MM/PBSA and MM/GBSA methods 5 Improved docking performance using high solute dielectric constant MM/GBSA and MM/PBSA rescoring. Phys Chem Chem Phys 16(40):22035–22045. https://doi.org/10.1039/C4CP03179B

    Article  CAS  PubMed  Google Scholar 

  55. Miller BR 3rd, McGee TD Jr, Swails JM, Homeyer N, Gohlke H, Roitberg AE (2012) MMPBSApy: An Efficient Program for End-State Free Energy Calculations. J Chem Theory Comput 8(9):3314–3321. https://doi.org/10.1021/ct300418h

    Article  CAS  PubMed  Google Scholar 

  56. Sitkoff D, Sharp KA, Honig B (1994) Accurate calculation of hydration free energies using macroscopic solvent models. J Phys Chem 98(7):1978–1988. https://doi.org/10.1021/j100058a043

    Article  CAS  Google Scholar 

  57. Pearlman DA, Connelly PR (1995) Determination of the differential effects of hydrogen bonding and water release on the binding of FK506 to native and Tyr82–>Phe82 FKBP-12 proteins using free energy simulations. J Mol Biol 248(3):696–717

    Article  CAS  PubMed  Google Scholar 

  58. Guo J, Wang X, Sun H, Liu H, Yao X (2012) The molecular basis of IGF-II/IGF2R recognition: a combined molecular dynamics simulation, free-energy calculation and computational alanine scanning study. J Mol Model 18(4):1421–1430. https://doi.org/10.1007/s00894-011-1159-4

    Article  CAS  PubMed  Google Scholar 

  59. Yang Y, Liu H, Yao X (2012) Understanding the molecular basis of MK2-p38alpha signaling complex assembly: insights into protein-protein interaction by molecular dynamics and free energy studies. Mol Biosyst 8(8):2106–2118. https://doi.org/10.1039/c2mb25042j

    Article  CAS  PubMed  Google Scholar 

  60. Pan D, Niu Y, Xue W, Bai Q, Liu H, Yao X (2016) Computational study on the drug resistance mechanism of hepatitis C virus NS5B RNA-dependent RNA polymerase mutants to BMS-791325 by molecular dynamics simulation and binding free energy calculations. Chemometer Intell Lab Syst 154:185–193. https://doi.org/10.1016/j.chemolab.2016.03.015

    Article  CAS  Google Scholar 

  61. Li L, Wei W, Jia WJ, Zhu Y, Zhang Y, Chen JH, Tian J, Liu H, He YX, Yao X (2017) Discovery of small molecules binding to the normal conformation of prion by combining virtual screening and multiple biological activity evaluation methods. J Comput Aided Mol Des 31(12):1053–1062. https://doi.org/10.1007/s10822-017-0086-6

    Article  CAS  PubMed  Google Scholar 

  62. Shi D, Zhou S, Liu X, Zhao C, Liu H (1862) Yao X (2018) Understanding the structural and energetic basis of PD-1 and monoclonal antibodies bound to PD-L1: A molecular modeling perspective. Biochim Biophys Acta Gen Subj 3:576–588. https://doi.org/10.1016/j.bbagen.2017.11.022

    Article  CAS  Google Scholar 

  63. Liu H, Yao X (2010) Molecular basis of the interaction for an essential subunit PA-PB1 in influenza virus RNA polymerase: insights from molecular dynamics simulation and free energy calculation. Mol Pharm 7(1):75–85. https://doi.org/10.1021/mp90013p

    Article  CAS  PubMed  Google Scholar 

  64. Rohrig UF, Zoete V, Michielin O (2017) The binding mode of N-Hydroxyamidines to indoleamine 2,3-Dioxygenase 1 (IDO1). Biochemistry 56(33):4323–4325. https://doi.org/10.1021/acs.biochem.7b00586

    Article  CAS  PubMed  Google Scholar 

  65. RoHrig UF, Loay A, Aurélien G, Pierre L, Vincent S, Didier C, Vincenzo C, Simpson AJG, Pierre V, Eynde BTJ, Den V (2010) Rational design of indoleamine 2,3-dioxygenase inhibitors. J Med Chem 53(3):1172–1189. https://doi.org/10.1021/jm9014718

    Article  CAS  PubMed  Google Scholar 

  66. Greco FA, Bournique A, Coletti A, Custodi C, Dolciami D, Carotti A, Macchiarulo A (2016) Docking studies and molecular dynamic simulations reveal different features of IDO1 structure. Mol Inform 35(8–9):449–459. https://doi.org/10.1002/minf.201501038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Rohrig UF, Majjigapu SR, Grosdidier A, Bron S, Stroobant V, Pilotte L, Colau D, Vogel P, Van den Eynde BJ, Zoete V, Michielin O (2012) Rational design of 4-aryl-1,2,3-triazoles for indoleamine 2,3-dioxygenase 1 inhibition. J Med Chem 55(11):5270–5290. https://doi.org/10.1021/jm300260v

    Article  CAS  PubMed  Google Scholar 

  68. Lu T, Chen F (2012) Multiwfn: a multifunctional wavefunction analyzer. J Comput Chem 33(5):580–592. https://doi.org/10.1002/jcc.22885

    Article  CAS  PubMed  Google Scholar 

  69. Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(1):33–38. https://doi.org/10.1016/0263-7855(96)00018-5

    Article  CAS  PubMed  Google Scholar 

  70. Gaspari P, Banerjee T, Malachowski WP, Muller AJ, Prendergast GC, DuHadaway J, Bennett S, Donovan AM (2006) Structure−activity study of brassinin derivatives as indoleamine 2,3-dioxygenase inhibitors. J Med Chem 49(2):684–692. https://doi.org/10.1021/jm0508888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 21775060).

Author information

Authors and Affiliations

  1. School of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China

    Huizhen Ge, Danfeng Shi, Xing Yang, Xiaorui Wang & Xiaojun Yao

  2. School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, 453007, China

    Longfei Mao & Jie Zhao

  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

    Yuwei Wang & Xiaojun Yao

  4. School of Pharmacy, Lanzhou University, Lanzhou, 730000, China

    Huanxiang Liu

Authors
  1. Huizhen Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Longfei Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jie Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuwei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Danfeng Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaorui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Huanxiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaojun Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaojun Yao.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

10822_2021_386_MOESM1_ESM.docx

Supplementary file1 Fig. S1 14 analogues of compound 1 identified by similarity searching. Fig. S2 The concentration-dependent inhibition of IDO1 activities for all active compounds. (DOCX 8571 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ge, H., Mao, L., Zhao, J. et al. Discovery of novel IDO1 inhibitors via structure-based virtual screening and biological assays. J Comput Aided Mol Des 35, 679–694 (2021). https://doi.org/10.1007/s10822-021-00386-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-021-00386-6

Keywords

Search

Navigation