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Biaryl scaffold-focused virtual screening for anti-aggregatory and neuroprotective effects in Alzheimer's disease.

ABSTRACT: BACKGROUND:Alzheimer's disease (AD) is a primary cause of dementia in ageing population affecting more than 35 million people around the globe. It is a chronic neurodegenerative disease caused by defected folding and aggregation of amyloid beta (A?) protein. A? is formed by the cleavage of membrane embedded amyloid precursor protein (APP) by using enzyme 'transmembrane aspartyl protease, ?-secretase'. Inhibition of ?-secretase is a viable strategy to prevent neurotoxicity in AD. Another strategy in the treatment of AD is inhibition of acetylcholinesterase. This inhibition reduces the degradation of acetylcholine and temporarily restores the cholinergic function of neurons and improves cognitive function. Monoamine oxidase and higher glutamate levels are also found to be linked with A? peptide related oxidative stress. Oxidative stress leads to reduced activity of glutamate synthase resulting in significantly higher level of glutamate in brain. The aim of this study is to perform in silico screening of a virtual library of biaryl scaffold containing compounds potentially used for the treatment of AD. Screening was done against the primary targets of AD therapeutics, acetylcholinesterase, ?-secretase (BACE1), Monoamine oxidases (MAO) and N-Methyl-D-aspartate (NMDA) receptor. Compounds were screened for their inhibitory potential by employing molecular docking approach using AutoDock vina. Binding energy scores were embodied in the heatmap to display varies strengths of interactions of the ligands targeting AD. RESULTS:Several ligands showed notable interaction with at least two targets, but the strong interaction with all the targets is shown by very few ligands. The pharmacokinetics of the interacting ligands was also predicted. The interacting ligands have good drug-likeness and brain availability essential for drugs with intracranial targets. CONCLUSION:These results suggest that biaryl scaffold may be pliable to drug development for neuroprotection in AD and that the synthesis of further analogues to optimize these properties should be considered.

SUBMITTER: Khalid S

PROVIDER: S-EPMC6234579 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Biaryl scaffold-focused virtual screening for anti-aggregatory and neuroprotective effects in Alzheimer's disease.

Khalid Sidra S Zahid Muhammad Ammar MA Ali Hussain H Kim Yeong S YS Khan Salman S

BMC neuroscience 20181113 1

<h4>Background</h4>Alzheimer's disease (AD) is a primary cause of dementia in ageing population affecting more than 35 million people around the globe. It is a chronic neurodegenerative disease caused by defected folding and aggregation of amyloid beta (Aβ) protein. Aβ is formed by the cleavage of membrane embedded amyloid precursor protein (APP) by using enzyme 'transmembrane aspartyl protease, β-secretase'. Inhibition of β-secretase is a viable strategy to prevent neurotoxicity in AD. Another ...[more]

PMID: 30424732

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Project description:BackgroundNeuroinflammation and the presence of amyloid beta protein (Aβ) and neurofibrillary tangles are key pathologies in Alzheimer's disease (AD). As a potent anti-amyloid and anti-inflammatory natural polyphenol, curcumin (Cur) could be potential therapies for AD. Unfortunately, poor solubility, instability in physiological fluids, and low bioavailability limit its clinical utility. Recently, different lipid modifications in the formulae of Cur have been developed that would enhance its therapeutic potential. For example, we have reported greater permeability and neuroprotection with solid lipid curcumin particles (SLCP) than with natural Cur in an in vitro model of AD. In the present study, we compared the Aβ aggregation inhibition, anti-amyloid, anti-inflammatory responses of Cur and or SLCP in both in vitro and in vivo models of AD. One-year-old 5xFAD-and age-matched wild-type mice were given intraperitoneal injections of Cur or SLCP (50 mg/kg body weight) for 2- or 5-days. Levels of Aβ aggregation, including oligomers and fibril formation, were assessed by dot blot assay, while Aβ plaque load and neuronal morphology in the pre-frontal cortex (PFC) and hippocampus were assayed by immunolabeling with Aβ-specific antibody and cresyl violet staining, respectively. In addition, neuroinflammation was assessed the immunoreactivity (IR) of activated astrocytes (GFAP) and microglia (Iba-1) in different brain areas. Finally, comparisons of solubility and permeability of Cur and SLCP were made in cultured N2a cells and in primary hippocampal neurons derived from E16 pups of 5xFAD mice.ResultsWe observed that relative to Cur, SLCP was more permeable, labeled Aβ plaques more effectively, and produced a larger decrease in Aβ plaque loads in PFC and dentate gyrus (DG) of hippocampus. Similarly, relative to Cur, SLCP produced a larger decrease of pyknotic, or tangle-like, neurons in PFC, CA1, and CA3 areas of hippocampus after 5 days of treatment. Both Cur and or SLCP significantly reduced GFAP-IR and Iba-1-IR in PFC, in the striatum as well as CA1, CA3, DG, subicular complex of hippocampus, and the entorhinal cortex in the 5xFAD mice after 5 days of treatment.ConclusionsThe use of SLCP provides more anti-amyloid, anti-inflammatory, and neuroprotective outcomes than does Cur in the 5xFAD mouse model of AD.

Dataset Information

Biaryl scaffold-focused virtual screening for anti-aggregatory and neuroprotective effects in Alzheimer's disease.

Publications

Biaryl scaffold-focused virtual screening for anti-aggregatory and neuroprotective effects in Alzheimer's disease.

Similar Datasets

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