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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageAmerican English
Article number13098
JournalINTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume23
Issue number21
DOIs
StatePublished - 28 Oct 2022

Keywords

  • acetylcholinesterase (AChE)
  • amyloid beta
  • dual inhibitors
  • enzyme inhibition
  • in silico
  • in vitro
  • in vivo
  • multi-targeting
  • β-secretase (BACE-1)

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Spectroscopy
  • Catalysis
  • Inorganic Chemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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