Allostery Inhibition of BACE1 by Psychotic and Meroterpenoid Drugs in Alzheimer's Disease Therapy

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-07, Vol.27 (14), p.4372
• Main Authors: Ugbaja, Samuel C, Lawal, Isiaka A, Abubakar, Bahijjahtu H, Mushebenge, Aganze G, Lawal, Monsurat M, Kumalo, Hezekiel M
• Format: Article
• Language: English
• Subjects: Active sites; Aged; allosteric inhibitor; Allosteric properties; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; BACE1; Binding; Dementia; Drug development; Drugs; Dynamic stability; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Global health; Humans; Inhibitors; Ligands; Molecular docking; Molecular Docking Simulation; Molecular dynamics; molecular dynamics (MD) simulations; Molecular Dynamics Simulation; multisite targeting; NMR; Nuclear magnetic resonance; Older people; Proteins; Public health; β-Site APP-cleaving enzyme 1
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27144372

In over a century since its discovery, Alzheimer's disease (AD) has continued to be a global health concern due to its incurable nature and overwhelming increase among older people. In this paper, we give an overview of the efforts of researchers towards identifying potent BACE1 exosite-binding antibodies and allosteric inhibitors. Herein, we apply computer-aided drug design (CADD) methods to unravel the interactions of some proposed psychotic and meroterpenoid BACE1 allosteric site inhibitors. This study is aimed at validating the allosteric potentials of these selected compounds targeted at BACE1 inhibition. Molecular docking, molecular dynamic (MD) simulations, and post-MD analyses are carried out on these selected compounds, which have been experimentally proven to exhibit allosteric inhibition on BACE1. The SwissDock software enabled us to identify more than five druggable pockets on the BACE1 structural surface using docking. Besides the active site region, a melatonin derivative (compound ) previously proposed as a BACE1 allostery inhibitor showed appreciable stability at eight different subsites on BACE1. Refinement with molecular dynamic (MD) simulations shows that the identified non-catalytic sites are potential allostery sites for compound . The allostery and binding mechanism of the selected potent inhibitors show that the smaller the molecule, the easier the attachment to several enzyme regions. This finding hereby establishes that most of these selected compounds failed to exhibit strong allosteric binding with BACE1 except for compound . We hereby suggest that further studies and additional identification/validation of other BACE1 allosteric compounds be done. Furthermore, this additional allosteric site investigation will help in reducing the associated challenges with designing BACE1 inhibitors while exploring the opportunities in the design of allosteric BACE1 inhibitors.