Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder. One of the important therapeutic approaches of AD is the inhibition of β-site APP cleaving enzyme-1 (BACE1). This enzyme plays a central role in the synthesis of the pathogenic β-amyloid peptides (Aβ) in Alzheimer’s disease. A group of potent BACE1 inhibitors with known X-ray structures (PDB ID 5i3X, 5i3Y, 5iE1, 5i3V, 5i3W, 4LC7, 3TPP) were studied by molecular dynamics simulation and binding energy calculation employing MM_GB(PB)SA. The calculated binding energies gave Kd values of 0.139 µM, 1.39 nM, 4.39 mM, 24.3 nM, 1.39 mM, 29.13 mM, and 193.07 nM, respectively. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. The Kd values are compared with experimental values and the structures are discussed in view of the energy contributions to binding. Drug likeness of these inhibitors is also discussed. Accommodation of ligands in the catalytic site of BACE1 is discussed depending on the type of fragment involved in each structure. Molecular dynamics (MD) simulations and energy studies were used to explore the recognition of the selected BACE1 inhibitors by Asp32, Asp228, and the hydrophobic flap. The results show that selective BACE1 inhibition may be due to the formation of strong electrostatic interactions with Asp32 and Asp228 and a large number of hydrogen bonds, in addition to π–π and van der Waals interactions with the amino acid residues located inside the catalytic cavity. Interactions with the ligands show a similar binding mode with BACE1. These results help to rationalize the design of selective BACE1 inhibitors.

Highlights

  • Alzheimer’s disease (AD) is a progressive, neurodegenerative disease of the brain

  • The results show that selective BACE1 inhibition may be due to the formation of strong electrostatic interactions with Asp32 and Asp228 and a large number of hydrogen bonds, in addition to π–π and van der Waals interactions with the amino acid residues located inside the catalytic cavity

  • The enzyme BACE1 initiates the cleavage of amyloid precursor protein (APP) at the β-secretase site, Aβ is released as a result of further cleavage of the BACE1-cleaved C-terminal APP fragment [1]

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Summary

Introduction

Alzheimer’s disease (AD) is a progressive, neurodegenerative disease of the brain. AD and the associated dementia are connected to amyloid plaque accumulated in the brain. Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is an aspartic protease enzyme fixed to the cell membrane; it acts to produce β-amyloid (Aβ) in the signaling pathways in Alzheimer’s disease (AD). Excessive accumulation Aβ is believed to induce pathological changes and causes dementia in brains of AD patients. The enzyme BACE1 initiates the cleavage of amyloid precursor protein (APP) at the β-secretase site, Aβ is released as a result of further cleavage of the BACE1-cleaved C-terminal APP fragment [1]. Blocking BACE1 proteolytic activity will suppress Aβ generation and reduce the formation of amyloid

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