title: Important Hydrogen Bond Networks in Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Design Revealed by Crystal Structures of Imidazoleisoindole Derivatives with IDO1.
abstract: Indoleamine 2,3-dioxygenase 1 (IDO1), promoting immune escape of tumors, is a therapeutic target for the cancer immunotherapy. A number of IDO1 inhibitors have been identified, but only limited structural biology studies of IDO1 inhibitors are available to provide insights on the binding mechanism of IDO1. In this study, we present the structure of IDO1 in complex with 24, a NLG919 analogue with potent activity. The complex structure revealed the imidazole nitrogen atom of 24 to coordinate with the heme iron, and the imidazoleisoindole core situated in pocket A with the 1-cyclohexylethanol moiety extended to pocket B to interact with the surrounding residues. Most interestingly, 24 formed an extensive hydrogen bond network with IDO1, which is a distinct feature of IDO1/24 complex structure and is not observed in the other IDO1 complex structures. Further structure-activity relationship, UV spectra, and structural biology studies of several analogues of 24 demonstrated that extensive hydrophobic interactions and the unique hydrogen bonding network contribute to the great potency of imidazoleisoindole derivatives. These results are expected to facilitate the structure-based drug design of new IDO inhibitors.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Peng
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Shau-Hua
authors.initials: SH
authors.lastname: Ueng
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Chen-Tso
authors.initials: CT
authors.lastname: Tseng
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Ming-Shiu
authors.initials: MS
authors.lastname: Hung
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Jen-Shin
authors.initials: JS
authors.lastname: Song
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Jian-Sung
authors.initials: JS
authors.lastname: Wu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Fang-Yu
authors.initials: FY
authors.lastname: Liao
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Yu-Shiou
authors.initials: YS
authors.lastname: Fan
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Mine-Hsine
authors.initials: MH
authors.lastname: Wu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Hsiao
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Ching-Cheng
authors.initials: CC
authors.lastname: Hsueh
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Lin
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Chih-Hsiang
authors.initials: CH
authors.lastname: Tu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Lung-Chun
authors.initials: LC
authors.lastname: Lee
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Ming-Fu
authors.initials: MF
authors.lastname: Cheng
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Kak-Shan
authors.initials: KS
authors.lastname: Shia
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Chuan
authors.initials: C
authors.lastname: Shih
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Wu
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; C576710:IDO1 protein, human; D007093:Imidazoles; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase