Novel Approach for the Search for Chemical Scaffolds with Activity at Both Acetylcholinesterase and the α7 Nicotinic Acetylcholine Receptor: A Perspective on Scaffolds with Dual Activity for the Treatment of Neurodegenerative Disorders
Neurodegenerative disorders, including Alzheimer’s 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 dis...
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| Format: | Article |
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MDPI AG
2019-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/3/446 |
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| author | Natalia M. Kowal Dinesh C. Indurthi Philip K. Ahring Mary Chebib Elin S. Olafsdottir Thomas Balle |
| author_facet | Natalia M. Kowal Dinesh C. Indurthi Philip K. Ahring Mary Chebib Elin S. Olafsdottir Thomas Balle |
| author_sort | Natalia M. Kowal |
| collection | DOAJ |
| description | Neurodegenerative disorders, including Alzheimer’s 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 α7 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, <b>8</b> and <b>9</b>, with dual activity and balanced IC<sub>50</sub> values of 10 and 5 µM at AChE, and 34 and 14 µM at α7 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 α7 nAChR and shows that computational methods can be a valuable tool in the early lead discovery process. |
| first_indexed | 2024-12-12T20:32:30Z |
| format | Article |
| id | doaj.art-55b8782016de4f24a5788f0d5b35b986 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-12T20:32:30Z |
| publishDate | 2019-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-55b8782016de4f24a5788f0d5b35b9862022-12-22T00:12:59ZengMDPI AGMolecules1420-30492019-01-0124344610.3390/molecules24030446molecules24030446Novel Approach for the Search for Chemical Scaffolds with Activity at Both Acetylcholinesterase and the α7 Nicotinic Acetylcholine Receptor: A Perspective on Scaffolds with Dual Activity for the Treatment of Neurodegenerative DisordersNatalia M. Kowal0Dinesh C. Indurthi1Philip K. Ahring2Mary Chebib3Elin S. Olafsdottir4Thomas Balle5Faculty of Pharmaceutical Sciences, School of Health Sciences, University of Iceland, 107 Reykjavik, IcelandSydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, AustraliaSydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, AustraliaSydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, AustraliaFaculty of Pharmaceutical Sciences, School of Health Sciences, University of Iceland, 107 Reykjavik, IcelandSydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, AustraliaNeurodegenerative disorders, including Alzheimer’s 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 α7 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, <b>8</b> and <b>9</b>, with dual activity and balanced IC<sub>50</sub> values of 10 and 5 µM at AChE, and 34 and 14 µM at α7 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 α7 nAChR and shows that computational methods can be a valuable tool in the early lead discovery process.https://www.mdpi.com/1420-3049/24/3/446virtual screeningmulti modaldual mode of actionnAChRnicotinic acetylcholine receptorAChEacetylcholinesterasedockinglead identificationneurodegenerative disorders |
| spellingShingle | Natalia M. Kowal Dinesh C. Indurthi Philip K. Ahring Mary Chebib Elin S. Olafsdottir Thomas Balle Novel Approach for the Search for Chemical Scaffolds with Activity at Both Acetylcholinesterase and the α7 Nicotinic Acetylcholine Receptor: A Perspective on Scaffolds with Dual Activity for the Treatment of Neurodegenerative Disorders Molecules virtual screening multi modal dual mode of action nAChR nicotinic acetylcholine receptor AChE acetylcholinesterase docking lead identification neurodegenerative disorders |
| title | Novel Approach for the Search for Chemical Scaffolds with Activity at Both Acetylcholinesterase and the α7 Nicotinic Acetylcholine Receptor: A Perspective on Scaffolds with Dual Activity for the Treatment of Neurodegenerative Disorders |
| title_full | Novel Approach for the Search for Chemical Scaffolds with Activity at Both Acetylcholinesterase and the α7 Nicotinic Acetylcholine Receptor: A Perspective on Scaffolds with Dual Activity for the Treatment of Neurodegenerative Disorders |
| title_fullStr | Novel Approach for the Search for Chemical Scaffolds with Activity at Both Acetylcholinesterase and the α7 Nicotinic Acetylcholine Receptor: A Perspective on Scaffolds with Dual Activity for the Treatment of Neurodegenerative Disorders |
| title_full_unstemmed | Novel Approach for the Search for Chemical Scaffolds with Activity at Both Acetylcholinesterase and the α7 Nicotinic Acetylcholine Receptor: A Perspective on Scaffolds with Dual Activity for the Treatment of Neurodegenerative Disorders |
| title_short | Novel Approach for the Search for Chemical Scaffolds with Activity at Both Acetylcholinesterase and the α7 Nicotinic Acetylcholine Receptor: A Perspective on Scaffolds with Dual Activity for the Treatment of Neurodegenerative Disorders |
| title_sort | novel approach for the search for chemical scaffolds with activity at both acetylcholinesterase and the α7 nicotinic acetylcholine receptor a perspective on scaffolds with dual activity for the treatment of neurodegenerative disorders |
| topic | virtual screening multi modal dual mode of action nAChR nicotinic acetylcholine receptor AChE acetylcholinesterase docking lead identification neurodegenerative disorders |
| url | https://www.mdpi.com/1420-3049/24/3/446 |
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