Emetine and Indirubin- 3- monoxime interaction with human brain acetylcholinesterase: A computational and statistical analysis.

Syed Sayeed Ahmad,Haroon Khan,Abdulraheem Sa Almalki,Mohammad Khalid

doi:10.14715/cmb/2021.67.4.12

Abstract

Alzheimer's disease is a chronic neurodegenerative ailment and the most familiar type of dementia in the older population with no effective cure to date. It is characterized by a decrease in memory, associated with the mutilation of cholinergic neurotransmission. Presently, acetylcholinesterase inhibitors have emerged as the most endorsed pharmacological medications for the symptomatic treatment of mild to moderate Alzheimer's disease. This study aimed to research the molecular enzymatic inhibition of human brain acetylcholinesterase by a natural compound emetine and I3M. Molecular docking studies were used to identify superior interaction between enzyme acetylcholinesterase and ligands. Furthermore, the docked acetylcholinesterase-emetine complex was validated statistically using an analysis of variance in all tested conformers. In this interaction, H-bond, hydrophobic interaction, pi-pi, and Cation-pi interactions played a vital function in predicting the accurate conformation of the ligand that binds with the active site of acetylcholinesterase. The conformer with the lowest free energy of binding was further analyzed. The binding energy for acetylcholinesterase complex with emetine and I3M was -9.72kcal/mol and -7.09kcal/mol, respectively. In the current study, the prediction was studied to establish a relationship between binding energy and intermolecular energy (coefficient of determination [R2 linear = 0.999), and intermolecular energy and Van der wall forces (R2 linear = 0.994). These results would be useful in gaining structural insight for designing novel lead compounds against acetylcholinesterase for the effective management of Alzheimer's disease.

Highlights

Alzheimer's disease is a chronic neurodegenerative ailment and the most familiar type of dementia in the older population with no effective cure to date
It has been reported that cholinergic neurotransmitter levels are significantly reduced under conditions such as Alzheimer’s disease (AD) [31, 32], AChE is typically targeted in terms of enzyme inhibition since this strategy temporarily increases ACh levels
The thought that cholinergic shortfalls are centrally connected with the pathogenesis of neurodegenerative conditions, for example, AD centers around the loss of cholinergic neurons and the following decrease of synapse levels [33]

Summary

Introduction

Alzheimer's disease is a chronic neurodegenerative ailment and the most familiar type of dementia in the older population with no effective cure to date. The prediction was studied to establish a relationship between binding energy and intermolecular energy (coefficient of determination [R2 linear = 0.999), and intermolecular energy and Van der wall forces (R2 linear = 0.994) These results would be useful in gaining structural insight for designing novel lead compounds against acetylcholinesterase for the effective management of Alzheimer's disease. Drastically affected, demonstrating restoration of AD is a dynamic and irreversible ND and the most acetylcholine (ACh) and different markers of widely recognized foundation of dementia in the older cholinergic activity [6] In light of this perception, the population > 60 years and the seventh leading cause medications galantamine [7], donepezil [8], and of death throughout the world [2, 3]. Cholinesterase inhibitors improve cholinergic action by restraining AChE that hydrolyze ACh following synaptic discharge and, prolongs the activity of ACh [15, 16]

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