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Inhibition Mechanism of Indoleamine 2, 3-Dioxygenase 1 (IDO1) by Amidoxime Derivatives and Its Revelation in Drug Design: Comparative Molecular Dynamics Simulations.

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机构： [1]Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China, [2]Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, College of Pharmacy and Biological Engineering, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China, [3]College of Mathematics and Informatics, South China Agricultural University, Guangzhou, China, 4 School of Electrical and Information Engineering, Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou, China

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关键词： indoleamine 2 3-dioxygenase 1 epacadostat molecular dynamic simulation inhibition mechanism revelation in drug design

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For cancer treatment, in addition to the three standard therapies of surgery, chemotherapy, and radiotherapy, immunotherapy has become the fourth internationally-recognized alternative treatment. Indoleamine 2, 3-dioxygenase 1 (IDO1) catalyzes the conversion of tryptophan to kynurenine causing lysine depletion, which is an important target in the research and development of anticancer drugs. Epacadostat (INCB024360) is currently one of the most potent IDO1 inhibitors, nevertheless its inhibition mechanism still remains elusive. In this work, comparative molecular dynamics simulations were performed to reveal that the high inhibitory activity of INCB024360 mainly comes from two aspects: disturbing the ligand delivery tunnel and then preventing small molecules such as oxygen and water molecules from accessing the active site, as well as hindering the shuttle of substrate tryptophan with product kynurenine through the heme binding pocket. The scanning of key residues showed that L234 and R231 residues both were crucial to the catalytic activity of IDO1. With the association with INCB024360, L234 forms a stable hydrogen bond with G262, which significantly affects the spatial position of G262-A264 loop and then greatly disturbs the orderliness of ligand delivery tunnel. In addition, the cleavage of hydrogen bond between G380 and R231 increases the mobility of the GTGG conserved region, leading to the closure of the substrate tryptophan channel. This work provides new ideas for understanding action mechanism of amidoxime derivatives, improving its inhibitor activity and developing novel inhibitors of IDO1. Copyright © 2020 Liu, Zhang, Duan, Luo, Liu, Liang, Wan, Chang, Hu and Shi.

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出版当年[2019]版：

大类 | 4 区生物学

小类 | 4 区生化与分子生物学

最新[2023]版：

大类 | 3 区生物学

小类 | 3 区生化与分子生物学

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第一作者机构： [1]Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China,

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Inhibition Mechanism of Indoleamine 2, 3-Dioxygenase 1 (IDO1) by Amidoxime Derivatives and Its Revelation in Drug Design: Comparative Molecular Dynamics Simulations.

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