Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs
| Autor: | Fanny C.F. Ip, Amy K.Y. Fu, Nancy Y. Ip, Xuhui Huang, Shuo Gu, Estella P.S. Tong, Wing Yu Fu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Drug media_common.quotation_subject Science Cyproheptadine Drug Evaluation Preclinical Mice Transgenic Context (language use) Plasma protein binding Pharmacology Ligands Hippocampus Article Receptor tyrosine kinase Mice 03 medical and health sciences Protein Domains Alzheimer Disease Animals Medicine Ephrin Receptor media_common Neurons Virtual screening Multidisciplinary biology business.industry Receptor EphA4 Bridged Bicyclo Compounds Heterocyclic Molecular Docking Simulation Disease Models Animal Pyrimidines 030104 developmental biology Nilotinib biology.protein Androstenes Diterpenes business Protein Binding medicine.drug |
| Zdroj: | Scientific Reports, Vol 8, Iss 1, Pp 1-7 (2018) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | The receptor tyrosine kinase, erythropoietin-producing hepatocellular A4 (EphA4), was recently identified as a molecular target for Alzheimer’s disease (AD). We found that blockade of the interaction of the receptor and its ligands, ephrins, alleviates the disease phenotype in an AD transgenic mouse model, suggesting that targeting EphA4 is a potential approach for developing AD interventions. In this study, we identified five FDA-approved drugs—ergoloid, cyproheptadine, nilotinib, abiraterone, and retapamulin—as potential inhibitors of EphA4 by using an integrated approach combining virtual screening with biochemical and cellular assays. We initially screened a database of FDA-approved drugs using molecular docking against the ligand-binding domain of EphA4. Then, we selected 22 candidate drugs and examined their inhibitory activity towards EphA4. Among them, five drugs inhibited EphA4 clustering induced by ephrin-A in cultured primary neurons. Specifically, nilotinib, a kinase inhibitor, inhibited the binding of EphA4 and ephrin-A at micromolar scale in a dosage-dependent manner. Furthermore, nilotinib inhibited the activation of EphA4 and EphA4-dependent growth cone collapse in cultured hippocampal neurons, demonstrating that the drug exhibits EphA4 inhibitory activity in cellular context. As demonstrated in our combined computational and experimental approaches, repurposing of FDA-approved drugs to inhibit EphA4 may provide an alternative fast-track approach for identifying and developing new treatments for AD. |
| Databáze: | OpenAIRE |
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