Discovery of 9-phenylacridinediones as highly selective butyrylcholinesterase inhibitors through structure-based virtual screening
| dc.contributor.author | Joubert, Jacques | |
| dc.contributor.author | Kapp, Erika | |
| dc.date.accessioned | 2021-12-08T09:57:12Z | |
| dc.date.available | 2021-12-08T09:57:12Z | |
| dc.date.issued | 2020 | |
| dc.description.abstract | Butyrylcholinesterase (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.citation | Joubert, 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.2020.127075 | en_US |
| dc.identifier.issn | 0960-894X | |
| dc.identifier.uri | https://doi.org/10.1016/j.bmcl.2020.127075 | |
| dc.identifier.uri | http://hdl.handle.net/10566/7064 | |
| dc.language.iso | en | en_US |
| dc.publisher | Elsevier | en_US |
| dc.subject | Alzheimer’s disease | en_US |
| dc.subject | Virtual screening | en_US |
| dc.subject | Docking | en_US |
| dc.subject | Mental health | en_US |
| dc.title | Discovery of 9-phenylacridinediones as highly selective butyrylcholinesterase inhibitors through structure-based virtual screening | en_US |
| dc.type | Article | en_US |