Novel 1,2,3-Triazole Erlotinib Derivatives as Potent IDO1 Inhibitors: Design, Drug-Target Interactions Prediction, Synthesis, Biological Evaluation, Molecular Docking and ADME Properties Studies

Gui-Qing Xu; Xiao-Qing Gong; Ying-Ying Zhu; Xiao-Jun Yao; Li-Zeng Peng; Ge Sun; Jian-Xue Yang; Long-Fei Mao

doi:10.3389/fphar.2022.854965

Novel 1,2,3-Triazole Erlotinib Derivatives as Potent IDO1 Inhibitors: Design, Drug-Target Interactions Prediction, Synthesis, Biological Evaluation, Molecular Docking and ADME Properties Studies

Front Pharmacol. 2022 May 23:13:854965. doi: 10.3389/fphar.2022.854965. eCollection 2022.

Authors

Gui-Qing Xu¹, Xiao-Qing Gong², Ying-Ying Zhu¹, Xiao-Jun Yao², Li-Zeng Peng³, Ge Sun⁴, Jian-Xue Yang^{5

6}, Long-Fei Mao^{1

3}

Affiliations

¹ Henan Engineering Research Center of Chiral Hydroxyl Pharmaceutical, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, China.
² College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China.
³ Key Laboratory of Agro-Products Processing Technology of Shandong Province, Key Laboratory of Novel Food Resources Processing Ministry of Agriculture, Institute of Agro-Food Science and Technology Shandong Academy of Agricultural Sciences, Jinan, China.
⁴ The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
⁵ Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China.
⁶ School of Nursing, Henan University of Science and Technology, Luoyang, China.

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) plays a predominant role in cancer immunotherapy which catalyzes the initial and rate limiting steps of the kynurenine pathway as a key enzyme. To explore novel IDO1 inhibitors, five derivatives of erlotinib-linked 1,2,3-triazole compounds were designed by using a structure-based drug design strategy. Drug-target interactions (DTI) were predicted by DeePurpose, an easy-to-use deep learning library that contains more than 50 algorithms. The DTI prediction results suggested that the designed molecules have potential inhibitory activities for IDO1. Chemical syntheses and bioassays showed that the compounds exhibited remarkable inhibitory activities against IDO1, among them, compound e was the most potent with an IC₅₀ value of 0.32 ± 0.07 μM in the Hela cell assay. The docking model and ADME analysis exhibited that the effective interactions of these compounds with heme iron and better drug-likeness ensured the IDO1 inhibitory activities. The studies suggested that compound e was a novel and interesting IDO1 inhibitor for further development.

Keywords: 1,2,3-triazole; ADME analysis; DTI; cell assay; docking; erlotinib.