Dehydrogenases are intracellular respiratory enzymes that catalyze redox reactions using one of the coenzymes, such as NAD+/NADP+ or flavins, namely FAD and FMN, as electron acceptors. Through this process, organic compounds undergo oxidation by transferring hydrogen atoms to these acceptors, resulting in energy production. Dehydrogenases are relevant targets in numerous conditions, including various types of cancer, neurodegenerative diseases, Alzheimer's disease, hormone-dependent disorders, viral infections, as well as steroid and lipid metabolism disorders [1-5].
Our cheminformatics team has developed dedicated Screening Sets employing ligand- and receptor-based approaches:
In total, over 5,500 drug-like screening compounds with predicted activity against dehydrogenases were selected from the Company’s HTS Compound Collection. The compound list was narrowed down by dissimilarity.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Background
As known, dehydrogenases belong to the oxidoreductase group. These enzymes catalyze reversible hydrogen transfer reactions, like ketone reduction, reductive amination, double bond reduction, alcohol oxidation, and aldehyde oxidation. Dehydrogenases play a significant role in the vital activity of animals, plants, and bacteria. In particular, potentially active dehydrogenase compounds can be used to combat a number of human and animal diseases. Also, they are utilized as herbicides, biosensors, etc. Figure 1 shows the classification of dehydrogenases according to their prosthetic group [6].
Figure 1. Classification of dehydrogenases according to their prosthetic group.
Dehydrogenase Focused Library
This ligand-based Screening Set was prepared through a 2D fingerprint similarity search against the HTS Compound Collection. A reference set based on the data published on dehydrogenases and their complex bioactivities as per the ChEMBL database was used. The minimum Tanimoto index > 0.85 allowed for the identification of over 6,000 structural analogs of reported nuclear receptor modulators. The resulting screening compound selection was reduced by dissimilarity to give 4,700 drug-like small molecules for dehydrogenase-related targets, shown below:
- Isocitrate dehydrogenase [NADP] cytoplasmic
- Glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase
- Aldehyde dehydrogenase
- L-lactate dehydrogenase A chain
- Pyruvate dehydrogenase kinase
- Pyruvate dehydrogenase kinase isoform 1
- Dihydroorotate dehydrogenase
- Sorbitol dehydrogenase
- Malate dehydrogenase
- Pyruvate dehydrogenase kinase isoform 2
- Glucose-6-phosphate 1-dehydrogenase
- Glyceraldehyde-3-phosphate dehydrogenase liver
- L-lactate dehydrogenase B chain
- Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial
- Malate dehydrogenase mitochondrial
- Malate dehydrogenase cytoplasmic
- Alcohol dehydrogenase
- Acyl-CoA dehydrogenase family member 11
- Pyruvate dehydrogenase kinase isoform 4
Figure 2. Compound distribution by general target classes within the Life Chemicals Dehydrogenase-focused Screening Library.
Representative screening compounds from the Dehydrogenase Focused Library
Dehydrogenase Targeted Library
This Screening Set comprises approximately 800 structurally diverse screening molecules with potential activity against dihydroorotate dehydrogenase. These drug-like compounds were identified through pharmacophore-based virtual screening. The number of potentially active compounds can be expanded upon request.
Dihydroorotate dehydrogenase (DHODH)
Human dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme that catalyzes the conversion of dihydroorotate to orotate with a quinone as an electron acceptor. It is a relevant therapeutic target for the treatment of rheumatoid arthritis and multiple sclerosis [1]. Today, it is actively being considered in the therapy of many types of cancer, such as acute myeloid leukemia, neuroblastoma, medulloblastoma, cervical cancer, etc. [7-12]. DHODH inhibition has also been shown to be effective in antiviral therapy (cytomegalovirus, Ebola virus, influenza, Epstein-Barr virus, picornavirus, and SARS-CoV-2) [13].
Key features:
- Method: Pharmacophore-based virtual screening
- X-Ray data used: 3G0U
- Filters used: no
- Number of compounds selected: 824
Figure 3. Pharmacophore hypothesis based on the complex of DHODH with leflunomide.
Reference:
- Price MJ, Nguyen AD, Byemerwa JK, Flowers J, Baëta CD, Goodwin CR. UDP-glucose dehydrogenase (UGDH) in clinical oncology and cancer biology. Oncotarget. 2023;14:843-857. Published 2023 Sep 28. doi:10.18632/oncotarget.28514
- He XY, Frackowiak J, Dobkin C, Brown WT, Yang SY. Involvement of Type 10 17β-Hydroxysteroid Dehydrogenase in the Pathogenesis of Infantile Neurodegeneration and Alzheimer's Disease. Int J Mol Sci. 2023;24(24):17604. Published 2023 Dec 18. doi:10.3390/ijms242417604
- Heinosalo T, Saarinen N, Poutanen M. Role of hydroxysteroid (17beta) dehydrogenase type 1 in reproductive tissues and hormone-dependent diseases. Mol Cell Endocrinol. 2019;489:9-31. doi:10.1016/j.mce.2018.08.004
- Gehlot P, Vyas VK. Recent advances on patents of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors as antimalarial agents. Expert Opin Ther Pat. 2023;33(9):579-596. doi:10.1080/13543776.2023.2280596
- Wang MX, Peng ZG. 17β-hydroxysteroid dehydrogenases in the progression of nonalcoholic fatty liver disease. Pharmacol Ther. 2023;246:108428. doi:10.1016/j.pharmthera.2023.108428
- Blank LM, Ebert BE, Buehler K, Bühler B. Redox biocatalysis and metabolism: molecular mechanisms and metabolic network analysis. Antioxid Redox Signal. 2010;13(3):349-394. doi:10.1089/ars.2009.2931
- Zhou Y, Tao L, Zhou X, et al. DHODH and cancer: promising prospects to be explored. Cancer Metab. 2021;9(1):22. Published 2021 May 10. doi:10.1186/s40170-021-00250-z
- Christian S, Merz C, Evans L, et al. The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies. Leukemia. 2019;33(10):2403-2415. doi:10.1038/s41375-019-0461-5
- Mao C, Liu X, Zhang Y, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer [published correction appears in Nature. 2021 Aug;596(7873):E13]. Nature. 2021;593(7860):586-590. doi:10.1038/s41586-021-03539-7
- Olsen TK, Dyberg C, Embaie BT, et al. DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma. JCI Insight. 2022;7(17):e153836. Published 2022 Aug 9. doi:10.1172/jci.insight.153836
- Jiang M, Song Y, Liu H, Jin Y, Li R, Zhu X. DHODH Inhibition Exerts Synergistic Therapeutic Effect with Cisplatin to Induce Ferroptosis in Cervical Cancer through Regulating mTOR Pathway. Cancers (Basel). 2023;15(2):546. Published 2023 Jan 16. doi:10.3390/cancers15020546
- Gwynne WD, Suk Y, Custers S, et al. Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma. Cancer Cell. 2022;40(12):1488-1502.e7. doi:10.1016/j.ccell.2022.10.009
- Kaur H, Sarma P, Bhattacharyya A, et al. Efficacy and safety of dihydroorotate dehydrogenase (DHODH) inhibitors "leflunomide" and "teriflunomide" in Covid-19: A narrative review. Eur J Pharmacol. 2021;906:174233. doi:10.1016/j.ejphar.2021.174233