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Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer's Disease: From In Silico to In Vivo.

ABSTRACT: 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 (IC₅₀ between 4-7 μM) and BACE-1 (IC₅₀ 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.

SUBMITTER: Stern N

PROVIDER: S-EPMC9655245 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer's Disease: From In Silico to In Vivo.

Stern Noa N Gacs Alexandra A Tátrai Enikő E Flachner Beáta B Hajdú István I Dobi Krisztina K Bágyi István I Dormán György G Lőrincz Zsolt Z Cseh Sándor S Kígyós Attila A Tóvári József J Goldblum Amiram A

International journal of molecular sciences 20221028 21

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 ...[more]

PMID: 36361906

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Project description:Based on their reported neuroprotective properties, vanilloids provide a good starting point for the synthesis of anti-Alzheimer's disease (AD) agents. In this context, nine new 1,2,3-triazole conjugates of vanilloids were synthesized via click chemistry. The compounds were tested for their effect on acetylcholine esterase (AChE) and amyloid-beta peptide (Aβ) aggregation. The triazole esters (E)-(1-(4-hydroxy-3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl 3-(4-hydroxy-3 methoxyphenyl)acrylate 9 and (1-(4-hydroxy-3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl-4-hydroxy-3-methoxybenzoate 8 displayed dual inhibitory activity for AChE and Aβ aggregation with IC50 values of 0.47/0.31 μM and 1.2/0.95 μM, respectively, as compared to donepezil (0.27 μM) and tacrine (0.41 μM), respectively. The results showed that the triazole ester moiety is more favorable for the activity than the triazole ether moiety. This could be attributed to the longer length of the spacer between the two vanillyl moieties in the triazole esters. Furthermore, the binding affinities and modes of the triazole esters 9 and 8 were examined against AChE and Aβ utilizing a combination of docking predictions and molecular dynamics (MD) simulations. Docking computations revealed promising binding affinity of triazole esters 9 and 8 as potential AChE, Aβ40, and Aβ42 inhibitors with docking scores of -10.4 and -9.4 kcal mol-1, -5.8 and -4.7 kcal mol-1, and -3.3 and -2.9 kcal mol-1, respectively. The stability and binding energies of triazole esters 9 and 8 complexed with AChE, Aβ40, and Aβ42 were measured and compared to donepezil and tacrine over 100 ns MD simulations. According to the estimated binding energies, compounds 9 and 8 displayed good binding affinities with AChE, Aβ42, and Aβ40 with average ΔG binding values of -32.9 and -31.8 kcal mol-1, -12.0 and -10.5 kcal mol-1, and -20.4 and -16.6 kcal mol-1, respectively. Post-MD analyses demonstrated high steadiness for compounds 9 and 8 with AChE and Aβ during the 100 ns MD course. This work suggests the triazole conjugate of vanilloids as a promising skeleton for developing multi-target potential AD therapeutics.

Dataset Information

Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer's Disease: From In Silico to In Vivo.

Publications

Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer's Disease: From In Silico to In Vivo.

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