Discovery of 9-phenylacridinediones as highly selective butyrylcholinesterase inhibitors through structure-based virtual screening

dc.contributor.authorJoubert, Jacques
dc.contributor.authorKapp, Erika
dc.date.accessioned2021-12-08T09:57:12Z
dc.date.available2021-12-08T09:57:12Z
dc.date.issued2020
dc.description.abstractButyrylcholinesterase (BuChE) is considered a promising drug target as it plays an important role in the pro-gression of late stage Alzheimer’s disease (AD). Two compound libraries were selected and 64 124 aminecontaining moieties were screened using a hierarchical virtual screening protocol to discover new selectiveBuChE inhibitors. From these and subsequent docking experiments, 9-phenylacridinedione (9-PAD) was iden-tified as a promising scaffold for selective inhibition of BuChE. Selected top dock scored 9-PADs were assayedand compounds3and6exhibited potent and highly selective human BuChE inhibition (IC50: 98 nM and 142 nM,respectively). Both molecules were also predicted to show sufficient brain permeability, not have any substantialtoxicities, especially hepatotoxicity, and no significantinvitrocytotoxicity against SH-SY5Y neuroblastoma cellsat concentrations up to 100 μM. These findings indicate that 9-PAD is a promising lead structure for the de-velopment of agents able to treat late stage AD.en_US
dc.identifier.citationJoubert, J., & Kapp, E. (2020). Discovery of 9-phenylacridinediones as highly selective butyrylcholinesterase inhibitors through structure-based virtual screening. Bioorganic & Medicinal Chemistry Letters ,30(9), 127075. https://doi.org/10.1016/j.bmcl.2020.127075en_US
dc.identifier.issn0960-894X
dc.identifier.urihttps://doi.org/10.1016/j.bmcl.2020.127075
dc.identifier.urihttp://hdl.handle.net/10566/7064
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.subjectAlzheimer’s diseaseen_US
dc.subjectVirtual screeningen_US
dc.subjectDockingen_US
dc.subjectMental healthen_US
dc.titleDiscovery of 9-phenylacridinediones as highly selective butyrylcholinesterase inhibitors through structure-based virtual screeningen_US
dc.typeArticleen_US

Files

Original bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
1-s2.0-S0960894X20301530-main.pdf
Size:
3.28 MB
Format:
Adobe Portable Document Format
Description:
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.71 KB
Format:
Item-specific license agreed upon to submission
Description: