Virtual screening, ADMET prediction, molecular docking, and dynamic simulation studies of natural products as BACE1 inhibitors for the management of Alzheimer's disease.

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
    • Publication Information:
      Original Publication: London : Nature Publishing Group, copyright 2011-
    • Subject Terms:
      Alzheimer Disease*/drug therapy ; Alzheimer Disease*/metabolism ; Amyloid Precursor Protein Secretases*/antagonists & inhibitors ; Amyloid Precursor Protein Secretases*/metabolism ; Amyloid Precursor Protein Secretases*/chemistry ; Aspartic Acid Endopeptidases*/antagonists & inhibitors ; Aspartic Acid Endopeptidases*/metabolism ; Aspartic Acid Endopeptidases*/chemistry ; Biological Products*/chemistry ; Biological Products*/pharmacology ; Biological Products*/therapeutic use; Humans ; Drug Evaluation, Preclinical ; Ligands ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Binding
    • Abstract:
      Alzheimer's disease (AD) is a degenerative neurological disorder that chronically and irreversibly affects memory, cognitive function, learning ability, and organizational skills. Numerous studies have demonstrated BACE1 as a critical therapeutic target for AD, emphasizing the need for specific inhibition of BACE1 to develop effective therapeutics. However, current BACE1 inhibitors have certain limitations. Therefore, the aim of this study was to identify potential novel candidates derived from natural products that can be utilized for the treatment of AD. To achieve this, 80,617 natural compounds from the ZINC database were subjected to virtual screening and subsequently filtered according to the rule of five (RO5), leading to the identification of 1,200 compounds. Subsequently, the 1,200 compounds underwent molecular docking studies against the BACE1 receptor, utilizing high-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) techniques to identify high-affinity ligands. Of the 50 ligands that exhibited the highest G-Scores in HTVS, further analysis was conducted using SP docking and scoring methods. This analysis led to the identification of seven ligands with enhanced binding affinities, which were then subjected to additional screening via XP docking and scoring. Finally, the stability of the most promising ligand in relation to BACE1 was assessed through molecular dynamics (MD) simulations. The computational screening demonstrated that the docking energy values for seven ligands binding to target enzymes ranged between - 6.096 and - 7.626 kcal/mol. Among these, ligand 2 (L2) exhibited the best binding energy at -7.626 kcal/mol with BACE1. MD simulations further confirmed the stability of the BACE1-L2 complex, emphasizing the formation of a robust interaction between L2 and the target enzymes. Additionally, pharmacokinetic and drug-likeness evaluations indicated that L2 is non-carcinogenic and able to permeate the blood-brain barrier (BBB). The findings of this study will contribute to narrowing down the selection of candidates for subsequent in vitro and in vivo testing.
      (© 2024. The Author(s).)
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    • Accession Number:
      EC 3.4.- (Amyloid Precursor Protein Secretases)
      EC 3.4.23.- (Aspartic Acid Endopeptidases)
      EC 3.4.23.46 (BACE1 protein, human)
      0 (Biological Products)
      0 (Ligands)
    • Publication Date:
      Date Created: 20241103 Date Completed: 20241103 Latest Revision: 20241107
    • Publication Date:
      20241108
    • Accession Number:
      PMC11531584
    • Accession Number:
      10.1038/s41598-024-75292-6
    • Accession Number:
      39488559