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

被引:5
作者
Ge, Huizhen [1 ]
Mao, Longfei [2 ]
Zhao, Jie [2 ]
Wang, Yuwei [3 ]
Shi, Danfeng [1 ]
Yang, Xing [1 ]
Wang, Xiaorui [1 ]
Liu, Huanxiang [4 ]
Yao, Xiaojun [1 ,3 ]
机构
[1] Lanzhou Univ, Sch Chem & Chem Engn, Lanzhou 730000, Peoples R China
[2] Henan Normal Univ, Sch Chem & Chem Engn, Xinxiang 453007, Henan, Peoples R China
[3] Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Macau Inst Appl Res Med & Hlth, Taipa, Macau, Peoples R China
[4] Lanzhou Univ, Sch Pharm, Lanzhou 730000, Peoples R China
基金
中国国家自然科学基金;
关键词
IDO1; inhibitor; Virtual screening; Molecular docking; Molecular dynamics simulations; MM-GBSA calculation; INDOLEAMINE 2,3-DIOXYGENASE 1; MOLECULAR-DYNAMICS SIMULATION; QUANTUM-CHEMICAL CALCULATIONS; CRYSTAL-STRUCTURES; RATIONAL DESIGN; FORCE-FIELD; CANCER; TRYPTOPHAN; BINDING; DERIVATIVES;
D O I
10.1007/s10822-021-00386-6
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 mu M and the most potent one (compound 1) with IC50 of 1.18 +/- 0.04 mu M. 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 mu M. 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.
引用
收藏
页码:679 / 694
页数:16
相关论文
共 70 条
[1]  
[Anonymous], 2015, SCHROD VERS 10 1
[2]   Identification of Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Based on a Phenylimidazole Scaffold [J].
Brant, Michael G. ;
Goodwin-Tindall, Jake ;
Stover, Kurt R. ;
Stafford, Paul M. ;
Wu, Fan ;
Meek, Autumn R. ;
Schiavini, Paolo ;
Wohnig, Stephanie ;
Weaver, Donald F. .
ACS MEDICINAL CHEMISTRY LETTERS, 2018, 9 (02) :131-136
[3]   The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy [J].
Brochez, Lieve ;
Chevolet, Ines ;
Kruse, Vibeke .
EUROPEAN JOURNAL OF CANCER, 2017, 76 :167-182
[4]   Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival [J].
Brody, Jonathan R. ;
Costantino, Christina L. ;
Berger, Adam C. ;
Sato, Takami ;
Lisanti, Michael P. ;
Yeo, Charles J. ;
Emmons, Robert V. ;
Witkiewicz, Agnieszka K. .
CELL CYCLE, 2009, 8 (12) :1930-1934
[5]   The Amber biomolecular simulation programs [J].
Case, DA ;
Cheatham, TE ;
Darden, T ;
Gohlke, H ;
Luo, R ;
Merz, KM ;
Onufriev, A ;
Simmerling, C ;
Wang, B ;
Woods, RJ .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 2005, 26 (16) :1668-1688
[6]   Expression Pattern and Clinicopathological Relevance of the Indoleamine 2,3-Dioxygenase 1/Tryptophan 2,3-Dioxygenase Protein in Colorectal Cancer [J].
Chen, I-Chien ;
Lee, Kuen-Haur ;
Hsu, Ying-Hua ;
Wang, Wei-Ran ;
Chen, Chuan-Mu ;
Cheng, Ya-Wen .
DISEASE MARKERS, 2016, 2016
[7]   A patent review of IDO1 inhibitors for cancer [J].
Cheong, Jae Eun ;
Ekkati, Anil ;
Sun, Lijun .
EXPERT OPINION ON THERAPEUTIC PATENTS, 2018, 28 (04) :317-330
[8]   Discovery of a novel ROCK2 inhibitor with anti-migration effects via docking and high-content drug screening [J].
Chong, Cheong-Meng ;
Kou, Man-Teng ;
Pan, Peichen ;
Zhou, Hefeng ;
Ai, Nana ;
Li, Chuwen ;
Zhong, Hai-Jing ;
Leung, Chung-Hang ;
Hou, Tingjun ;
Lee, Simon Ming-Yuen .
MOLECULAR BIOSYSTEMS, 2016, 12 (09) :2713-2721
[9]   New Inhibitors of Indoleamine 2,3-Dioxygenase 1: Molecular Modeling Studies, Synthesis, and Biological Evaluation [J].
Coluccia, Antonio ;
Passacantilli, Sara ;
Famiglini, Valeria ;
Sabatino, Manuela ;
Patsilinakos, Alexandros ;
Ragno, Rino ;
Mazzoccoli, Carmela ;
Sisinni, Lorenza ;
Okuno, Alato ;
Takikawa, Osamu ;
Silvestri, Romano ;
La Regina, Giuseppe .
JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (21) :9760-9773
[10]   Tryptophan in health and disease [J].
Comai, Stefano ;
Bertazzo, Antonella ;
Brughera, Martina ;
Crotti, Sara .
ADVANCES IN CLINICAL CHEMISTRY, VOL 95, 2020, 95 :165-218