{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T08:57:15Z","timestamp":1767085035214,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2019,1,27]],"date-time":"2019-01-27T00:00:00Z","timestamp":1548547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1069417"],"award-info":[{"award-number":["APP1069417"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","award":["LP140100781"],"award-info":[{"award-number":["LP140100781"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Icelandic Research Fund","award":["152604053"],"award-info":[{"award-number":["152604053"]}]},{"name":"Bergthoru and Thorsteins Scheving Thorsteinsson Fund","award":["N.A."],"award-info":[{"award-number":["N.A."]}]},{"DOI":"10.13039\/501100005415","name":"H\u00e1sk\u00f3li \u00cdslands","doi-asserted-by":"publisher","award":["N.A."],"award-info":[{"award-number":["N.A."]}],"id":[{"id":"10.13039\/501100005415","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Neurodegenerative disorders, including Alzheimer\u2019s disease, belong to the group of the most difficult and challenging conditions with very limited treatment options. Attempts to find new drugs in most cases fail at the clinical stage. New tactics to develop better drug candidates to manage these diseases are urgently needed. It is evident that better understanding of the neurodegeneration process is required and targeting multiple receptors may be essential. Herein, we present a novel approach, searching for dual active compounds interacting with acetylcholinesterase (AChE) and the \u03b17 nicotinic acetylcholine receptor (nAChR) using computational chemistry methods including homology modelling and high throughput virtual screening. Activities of identified hits were evaluated at the two targets using the colorimetric method of Ellman and two-electrode voltage-clamp electrophysiology, respectively. Out of 87,250 compounds from a ZINC database of natural products and their derivatives, we identified two compounds, 8 and 9, with dual activity and balanced IC50 values of 10 and 5 \u00b5M at AChE, and 34 and 14 \u00b5M at \u03b17 nAChR, respectively. This is the first report presenting successful use of virtual screening in finding compounds with dual mode of action inhibiting both the AChE enzyme and the \u03b17 nAChR and shows that computational methods can be a valuable tool in the early lead discovery process.<\/jats:p>","DOI":"10.3390\/molecules24030446","type":"journal-article","created":{"date-parts":[[2019,1,29]],"date-time":"2019-01-29T03:40:55Z","timestamp":1548733255000},"page":"446","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Novel Approach for the Search for Chemical Scaffolds with Activity at Both Acetylcholinesterase and the \u03b17 Nicotinic Acetylcholine Receptor: A Perspective on Scaffolds with Dual Activity for the Treatment of Neurodegenerative Disorders"],"prefix":"10.3390","volume":"24","author":[{"given":"Natalia","family":"Kowal","sequence":"first","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, School of Health Sciences, University of Iceland, 107 Reykjavik, Iceland"},{"name":"Sydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia"},{"name":"Brain and Mind Centre, The University of Sydney, Camperdown, NSW 2050, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3699-9154","authenticated-orcid":false,"given":"Dinesh","family":"Indurthi","sequence":"additional","affiliation":[{"name":"Sydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia"},{"name":"Brain and Mind Centre, The University of Sydney, Camperdown, NSW 2050, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip","family":"Ahring","sequence":"additional","affiliation":[{"name":"Sydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia"},{"name":"Brain and Mind Centre, The University of Sydney, Camperdown, NSW 2050, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary","family":"Chebib","sequence":"additional","affiliation":[{"name":"Sydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia"},{"name":"Brain and Mind Centre, The University of Sydney, Camperdown, NSW 2050, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elin","family":"Olafsdottir","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, School of Health Sciences, University of Iceland, 107 Reykjavik, Iceland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Balle","sequence":"additional","affiliation":[{"name":"Sydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia"},{"name":"Brain and Mind Centre, The University of Sydney, Camperdown, NSW 2050, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1016\/S1474-4422(12)70228-4","article-title":"Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer\u2019s disease in the presenilin 1 E280A kindred: A case-control study","volume":"11","author":"Reiman","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17s","DOI":"10.1177\/0091270006288735","article-title":"Rationale for combination therapy with galantamine and memantine in Alzheimer\u2019s disease","volume":"46","author":"Grossberg","year":"2006","journal-title":"J. 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