Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer’s Disease: From In Silico to In Vivo
Alzheimer’s disease (AD) is a complex and widespread condition, still not fully understood and with no cure yet. Amyloid beta (Aβ) peptide is suspected to be a major cause of AD, and therefore, simultaneously blocking its formation and aggregation by inhibition of the enzymes BACE-1 (β-secretase) an...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/21/13098 |
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| author | Noa Stern Alexandra Gacs Enikő Tátrai Beáta Flachner István Hajdú Krisztina Dobi István Bágyi György Dormán Zsolt Lőrincz Sándor Cseh Attila Kígyós József Tóvári Amiram Goldblum |
| author_facet | Noa Stern Alexandra Gacs Enikő Tátrai Beáta Flachner István Hajdú Krisztina Dobi István Bágyi György Dormán Zsolt Lőrincz Sándor Cseh Attila Kígyós József Tóvári Amiram Goldblum |
| author_sort | Noa Stern |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is a complex and widespread condition, still not fully understood and with no cure yet. Amyloid beta (Aβ) peptide is suspected to be a major cause of AD, and therefore, simultaneously blocking its formation and aggregation by inhibition of the enzymes BACE-1 (β-secretase) and AChE (acetylcholinesterase) by a single inhibitor may be an effective therapeutic approach, as compared to blocking one of these targets or by combining two drugs, one for each of these targets. We used our ISE algorithm to model each of the AChE peripheral site inhibitors and BACE-1 inhibitors, on the basis of published data, and constructed classification models for each. Subsequently, we screened large molecular databases with both models. Top scored molecules were docked into AChE and BACE-1 crystal structures, and 36 Molecules with the best weighted scores (based on ISE indexes and docking results) were sent for inhibition studies on the two enzymes. Two of them inhibited both AChE (IC<sub>50</sub> between 4–7 μM) and BACE-1 (IC<sub>50</sub> between 50–65 μM). Two additional molecules inhibited only AChE, and another two molecules inhibited only BACE-1. Preliminary testing of inhibition by F681-0222 (molecule 2) on APPswe/PS1dE9 transgenic mice shows a reduction in brain tissue of soluble Aβ42. |
| first_indexed | 2024-03-09T19:00:18Z |
| format | Article |
| id | doaj.art-1abb183cf6ba4759a6369c1888c2b34f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T19:00:18Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1abb183cf6ba4759a6369c1888c2b34f2023-11-24T05:02:47ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123211309810.3390/ijms232113098Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer’s Disease: From In Silico to In VivoNoa Stern0Alexandra Gacs1Enikő Tátrai2Beáta Flachner3István Hajdú4Krisztina Dobi5István Bágyi6György Dormán7Zsolt Lőrincz8Sándor Cseh9Attila Kígyós10József Tóvári11Amiram Goldblum12Molecular Modeling and Drug Design Lab, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem 9112001, IsraelDepartment of Experimental Pharmacology, National Institute of Oncology, H-1122 Budapest, HungaryDepartment of Experimental Pharmacology, National Institute of Oncology, H-1122 Budapest, HungaryTargetEx Ltd., H-2120 Dunakeszi, HungaryTargetEx Ltd., H-2120 Dunakeszi, HungaryTargetEx Ltd., H-2120 Dunakeszi, HungaryTargetEx Ltd., H-2120 Dunakeszi, HungaryTargetEx Ltd., H-2120 Dunakeszi, HungaryTargetEx Ltd., H-2120 Dunakeszi, HungaryTargetEx Ltd., H-2120 Dunakeszi, HungaryKINETO Lab Ltd., H-1032 Budapest, HungaryKINETO Lab Ltd., H-1032 Budapest, HungaryMolecular Modeling and Drug Design Lab, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem 9112001, IsraelAlzheimer’s disease (AD) is a complex and widespread condition, still not fully understood and with no cure yet. Amyloid beta (Aβ) peptide is suspected to be a major cause of AD, and therefore, simultaneously blocking its formation and aggregation by inhibition of the enzymes BACE-1 (β-secretase) and AChE (acetylcholinesterase) by a single inhibitor may be an effective therapeutic approach, as compared to blocking one of these targets or by combining two drugs, one for each of these targets. We used our ISE algorithm to model each of the AChE peripheral site inhibitors and BACE-1 inhibitors, on the basis of published data, and constructed classification models for each. Subsequently, we screened large molecular databases with both models. Top scored molecules were docked into AChE and BACE-1 crystal structures, and 36 Molecules with the best weighted scores (based on ISE indexes and docking results) were sent for inhibition studies on the two enzymes. Two of them inhibited both AChE (IC<sub>50</sub> between 4–7 μM) and BACE-1 (IC<sub>50</sub> between 50–65 μM). Two additional molecules inhibited only AChE, and another two molecules inhibited only BACE-1. Preliminary testing of inhibition by F681-0222 (molecule 2) on APPswe/PS1dE9 transgenic mice shows a reduction in brain tissue of soluble Aβ42.https://www.mdpi.com/1422-0067/23/21/13098multi-targetingacetylcholinesterase (AChE)β-secretase (BACE-1)dual inhibitorsin silicoenzyme inhibition |
| spellingShingle | Noa Stern Alexandra Gacs Enikő Tátrai Beáta Flachner István Hajdú Krisztina Dobi István Bágyi György Dormán Zsolt Lőrincz Sándor Cseh Attila Kígyós József Tóvári Amiram Goldblum Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer’s Disease: From In Silico to In Vivo International Journal of Molecular Sciences multi-targeting acetylcholinesterase (AChE) β-secretase (BACE-1) dual inhibitors in silico enzyme inhibition |
| title | Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer’s Disease: From In Silico to In Vivo |
| title_full | Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer’s Disease: From In Silico to In Vivo |
| title_fullStr | Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer’s Disease: From In Silico to In Vivo |
| title_full_unstemmed | Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer’s Disease: From In Silico to In Vivo |
| title_short | Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer’s Disease: From In Silico to In Vivo |
| title_sort | dual inhibitors of ache and bace 1 for reducing aβ in alzheimer s disease from in silico to in vivo |
| topic | multi-targeting acetylcholinesterase (AChE) β-secretase (BACE-1) dual inhibitors in silico enzyme inhibition |
| url | https://www.mdpi.com/1422-0067/23/21/13098 |
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