Abstract
Ten acridones isolated from Atalantia monophylla were evaluated for effects on Alzheimer’s disease pathogenesis including antioxidant effects, acetylcholinesterase (AChE) inhibition, prevention of beta-amyloid (Aβ) aggregation and neuroprotection. To understand the mechanism, the type of AChE inhibition was investigated in vitro and binding interactions between acridones and AChE or Aβ were explored in silico. Drug-likeness and ADMET parameters were predicted in silico using SwissADME and pKCSM programs, respectively. All acridones showed favorable drug-likeness and possessed multifunctional activities targeting AChE function, Aβ aggregation and oxidation. All acridones inhibited AChE in a mixed-type manner and bound AChE at both catalytic anionic and peripheral anionic sites. In silico analysis showed that acridones interfered with Aβ aggregation by interacting at the central hydrophobic core, C-terminal hydrophobic region, and the key residues 41 and 42. Citrusinine II showed potent multifunctional action with the best ADMET profile and could alleviate neuronal cell damage induced by hydrogen peroxide and Aβ1-42 toxicity.
Highlights
Introduction published maps and institutional affilAlzheimer’s disease (AD) is a complex neurodegenerative disease that has a slow and irreversible progression
In the drug discovery process, it has been reported that 95% of drug candidate molecules fail in the development stages, and 50% of such failures are caused by unsatisfactory physicochemical and ADMET properties
Ten acridones isolated from Atalantia monophylla, namely N-methylatalaphylline, atalaphylline, N-methylatalaphyllinine, atalaphyllinine, N-methylcycloatalaphylline A, citrusinine I, citrusinine II, glycosparvarine, citruscridone, and buxifoliadine C, were filtered for their drug-likeness properties and evaluated for their activities in three AD
Summary
Introduction published maps and institutional affilAlzheimer’s disease (AD) is a complex neurodegenerative disease that has a slow and irreversible progression. AD symptoms are the result of brain structure changes in the hippocampus and cerebral cortex. The hippocampus is essential for learning and memory, which is susceptible to damage at early stages of AD, and the disturbance of cerebral cortex function affects orientation in space, language and memory [1]. The neuropathological features of AD include the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles, the reduction of acetylcholine (ACh) level and oxidative stress, all leading to the loss of synapse and neuron function [2,3,4]. The formation of amyloid senile plaques is accepted to be a key feature of Alzheimer’s disease pathogenesis [5]. The major component of the senile plaques is Aβ peptides, which are derived from the proteolytic processing of β-amyloid precursor protein (APP)
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