Research Paper Volume 14, Issue 13 pp 5478—5492
Computational study on novel natural compound inhibitor targeting IDH1_R132H
- 1 Department of Oncology, First People's Hospital of Xinxiang, Xin Xiang 453100, China
- 2 Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical College, Xin Xiang 453100, China
- 3 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xinxiang Medical College, Xin Xiang 453100, China
- 4 Department of Emergency, The First Affiliated Hospital of Xinxiang Medical College, Xin Xiang 453100, China
Received: September 17, 2021 Accepted: June 27, 2022 Published: July 7, 2022
https://doi.org/10.18632/aging.204162How to Cite
Copyright: © 2022 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Isocitrate dehydrogenases (IDH) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. IDH1 mutation has been reported in various tumors especially Cholangiocarcinoma, while the IDH1_R132H is reported to be the most common mutation of IDH1. IDH1_R132H inhibitors are effective anti-cancer drugs and have shown significant therapeutic effects in clinical. In this study, two novel natural compounds were identified to combine respectively with IDH1_R132H with a stronger binding force with conductive to interaction energy. They also showed low toxicity potential. Molecular dynamics simulation analysis demonstrated that the candidate ligands-IDH1_R132H complexes is stable in natural circumstances with favorable potential energy. Thus, Styraxlignolide F and Tremulacin were screened as promising IDH1_R132H inhibitors. We provide a solid foundation for the design and development of IDH1_R132H targeted drugs.
Abbreviations
2-HG: 2-hydroxyglutarate; AMES: Ames mutagenicity; ADME: Absorption, Distribution, Metabolism, and Excretion; BBB: Blood-brain barrier; CYP2D6: Cytochrome P4502D6; DS: Discovery Studio; DTP: Developmental toxicity potential; PPB: Plasma protein binding; IDH1: Isocitrate dehydrogenase 1; IDH2: Isocitrate dehydrogenase 2; NTP: National Toxicology Program; NADPH: Nicotinamide adenine dinucleotide phosphate; RMSD: Root-mean-square deviation.