dc.contributor |
Háskóli Íslands |
dc.contributor |
University of Iceland |
dc.contributor.author |
Oddsson, Sebastian |
dc.contributor.author |
Kowal, Natalia Magdalena |
dc.contributor.author |
Ahring, Philip K. |
dc.contributor.author |
Olafsdottir, Elin Soffia |
dc.contributor.author |
Balle, Thomas |
dc.date.accessioned |
2021-01-11T10:36:02Z |
dc.date.available |
2021-01-11T10:36:02Z |
dc.date.issued |
2020-06-22 |
dc.identifier.citation |
Oddsson, S.; Kowal, N.M.; Ahring, P.K.; Olafsdottir, E.S.; Balle, T. Structure-Based Discovery of Dual-Target Hits for Acetylcholinesterase and the α7 Nicotinic Acetylcholine Receptors: In Silico Studies and In Vitro Confirmation. Molecules 2020, 25, 2872. |
dc.identifier.issn |
1420-3049 |
dc.identifier.uri |
https://hdl.handle.net/20.500.11815/2337 |
dc.description |
Publisher's version (útgefin grein) |
dc.description.abstract |
Despite extensive efforts in the development of drugs for complex neurodegenerative diseases, treatment often remains challenging or ineffective, and hence new treatment strategies are necessary. One approach is the design of multi-target drugs, which can potentially address the complex nature of disorders such as Alzheimer’s disease. We report a method for high throughput virtual screening aimed at identifying new dual target hit molecules. One of the identified hits, N,N-dimethyl-1-(4-(3-methyl-[1,2,4]triazolo[4,3-a]pyrimidin-6-yl)phenyl)ethan-1-amine (Ýmir-2), has dual-activity as an acetylcholinesterase (AChE) inhibitor and as an α7 nicotinic acetylcholine receptor (α7 nAChR) agonist. Using computational chemistry methods, parallel and independent screening of a virtual compound library consisting of 3,848,234 drug-like and commercially available molecules from the ZINC15 database, resulted in an intersecting set of 57 compounds, that potentially possess activity at both of the two protein targets. Based on ligand efficiency as well as scaffold and molecular diversity, 16 of these compounds were purchased for in vitro validation by Ellman’s method and two-electrode voltage-clamp electrophysiology. Ýmir-2 was shown to exhibit the desired activity profile (AChE IC50 = 2.58 ± 0.96 µM; α7 nAChR activation = 7.0 ± 0.9% at 200 µM) making it the first reported compound with this particular profile and providing further evidence of the feasibility of in silico methods for the identification of novel multi-target hit molecules. |
dc.description.sponsorship |
This research was supported by the Icelandic Centre for Research [grant number: 152604], doctoral grant and financial support from the University of Iceland. |
dc.format.extent |
2872 |
dc.language.iso |
en |
dc.publisher |
MDPI AG |
dc.relation.ispartofseries |
Molecules;25(12) |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.subject |
Acetylcholinesterase |
dc.subject |
Alzheimer’s disease |
dc.subject |
Dual mode of action |
dc.subject |
Dual-target lead discovery |
dc.subject |
High-throughput virtual screening |
dc.subject |
Molecular docking |
dc.subject |
Alzheimer sjúkdómur |
dc.subject |
Lyfjagerð |
dc.title |
Structure-Based Discovery of Dual-Target Hits for Acetylcholinesterase and the α7 Nicotinic Acetylcholine Receptors: In Silico Studies and In Vitro Confirmation |
dc.type |
info:eu-repo/semantics/article |
dcterms.license |
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited |
dc.description.version |
Peer Reviewed |
dc.identifier.journal |
Molecules |
dc.identifier.doi |
10.3390/molecules25122872 |
dc.relation.url |
https://www.mdpi.com/1420-3049/25/12/2872/pdf |
dc.contributor.department |
Lyfjafræðideild (HÍ) |
dc.contributor.department |
Faculty of Pharmaceutical Sciences (UI) |
dc.contributor.school |
Heilbrigðisvísindasvið (HÍ) |
dc.contributor.school |
School of Health Sciences (UI) |