Decoding Conformational Imprint of Convoluted Molecular Interactions Between Prenylflavonoids and Aggregated Amyloid-Beta42 Peptide Causing Alzheimer's Disease.

E Srinivasan,Rohini Karunakaran,Iftikhar Aslam Tayubi,R Rajasekaran,P Chandrasekar,K Anbarasu,G Chandrasekhar,As Vickram

doi:10.3389/fchem.2021.753146

E Srinivasan, Rohini Karunakaran + Show 6 more

Open Access

https://doi.org/10.3389/fchem.2021.753146

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Abstract

Protein misfolding occurs due to the loss of native protein structure and adopts an abnormal structure, wherein the misfolded proteins accumulate and form aggregates, which result in the formation of amyloid fibrils that are associated with neurodegenerative diseases. Amyloid beta (Aβ42) aggregation or amyloidosis is contemplated as a unique hallmark characteristic of Alzheimer’s disease (AD). Due to aberrant accrual and aggregation of Aβ42 in extracellular space, the formation of senile plaques is found in AD patients. These senile plaques occur usually in the cognitive and memory region of the brain, enfeebles neurodegeneration, hinders the signaling between synapse, and disrupts neuronal functioning. In recent years, herbal compounds are identified and characterized for their potential as Aβ42 inhibitors. Thus, understanding their structure and molecular mechanics can provide an incredible finding in AD therapeutics. To describe the structure-based molecular studies in the rational designing of drugs against amyloid fibrils, we examined various herbal compounds that belong to prenylflavonoids. The present study characterizes the trends we identified at molecular docking studies and dynamics simulation where we observed stronger binding orientation of bavachalcone, bavachin, and neobavaisoflavone with the amyloid-beta (Aβ42) fibril structure. Hence, we could postulate that these herbal compounds could be potential inhibitors of Aβ42 fibrils; these anti-aggregation agents need to be considered in treating AD.

Highlights

Alzheimer’s disease (AD) is the archetypal impetus behind the mental deterioration of people over the age of 50, categorized as debilitative neurodegenerative disorder (Finder, 2010)
The herbal compounds, bavachalcone, bavachin, and neobavaisoflavone were embedded in the active site of the Aβ42 receptor as the best docked complex based on binding orientation (Table 1)
The docked complex of Aβ42bavachalcone exhibits about −8.23 kcal/mol binding energy, while bavachin and neobavaisoflavone exhibited −8.10 and −8.09 kcal/mol binding energy, respectively

Summary

Introduction

Alzheimer’s disease (AD) is the archetypal impetus behind the mental deterioration of people over the age of 50, categorized as debilitative neurodegenerative disorder (Finder, 2010). Aβ42 constitutes the majority of intraneuronal Aβ (Chen et al, 2017) These amyloid-beta oligomers form extracellular senile plaque deposits, protofibrils, and small oligomers with harmful effects such as synaptic damage, mitochondrial dysfunction, injury or dysfunction of neuronal cells, and death of neuronal cells that cause shrinkage and functional changes in the brain. This process is known as Amyloid cascade hypothesis, a hallmark in AD (Pimplikar, 2009; Reitz, 2012; Ricciarelli and Fedele, 2017). These aberrant proteins are supposed to be degraded by the ubiquitin (Ub)–proteasome system (UPS) and chaperone-mediated autophagy (CMA) pathways; under obscure circumstances, amyloid eludes the proteolytic pathways and furthers its accumulation in neuronal cells (Ciechanover and Kwon, 2015)

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