Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs

Abstract 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 transge...

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Autores principales:	Shuo Gu, Wing-Yu Fu, Amy K. Y. Fu, Estella Pui Sze Tong, Fanny C. F. Ip, Xuhui Huang, Nancy Y. Ip
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/685192b840f44ae194276059f135d92a
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spelling	oai:doaj.org-article:685192b840f44ae194276059f135d92a2021-12-02T15:07:57ZIdentification of new EphA4 inhibitors by virtual screening of FDA-approved drugs10.1038/s41598-018-25790-12045-2322https://doaj.org/article/685192b840f44ae194276059f135d92a2018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25790-1https://doaj.org/toc/2045-2322Abstract 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.Shuo GuWing-Yu FuAmy K. Y. FuEstella Pui Sze TongFanny C. F. IpXuhui HuangNancy Y. IpNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-7 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shuo Gu Wing-Yu Fu Amy K. Y. Fu Estella Pui Sze Tong Fanny C. F. Ip Xuhui Huang Nancy Y. Ip Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs
description	Abstract 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.
format	article
author	Shuo Gu Wing-Yu Fu Amy K. Y. Fu Estella Pui Sze Tong Fanny C. F. Ip Xuhui Huang Nancy Y. Ip
author_facet	Shuo Gu Wing-Yu Fu Amy K. Y. Fu Estella Pui Sze Tong Fanny C. F. Ip Xuhui Huang Nancy Y. Ip
author_sort	Shuo Gu
title	Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs
title_short	Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs
title_full	Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs
title_fullStr	Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs
title_full_unstemmed	Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs
title_sort	identification of new epha4 inhibitors by virtual screening of fda-approved drugs
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/685192b840f44ae194276059f135d92a
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Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs

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