Integration of System Biology Tools to Investigate Huperzine A as an Anti-Alzheimer Agent.

Pukar Khanal,Parveen Bansal,Dharmendra Kumar,Yasir K Mahdi,Ranjit Singh,Yadu Nandan Dey,Bahareh Farasati Far,Mogana R,Najwan K Jubair,Shailendra K Saraf,Malarvili Selvaraja,Farshid Zargari

doi:10.3389/fphar.2021.785964

Abstract

Aim: The present study aimed to investigate huperzine A as an anti-Alzheimer agent based on the principle that a single compound can regulate multiple proteins and associated pathways, using system biology tools. Methodology: The simplified molecular-input line-entry system of huperzine A was retrieved from the PubChem database, and its targets were predicted using SwissTargetPrediction. These targets were matched with the proteins deposited in DisGeNET for Alzheimer disease and enriched in STRING to identify the probably regulated pathways, cellular components, biological processes, and molecular function. Furthermore, huperzine A was docked against acetylcholinesterase using AutoDock Vina, and simulations were performed with the Gromacs package to take into account the dynamics of the system and its effect on the stability and function of the ligands. Results: A total of 100 targets were predicted to be targeted by huperzine A, of which 42 were regulated at a minimum probability of 0.05. Similarly, 101 Kyoto Encyclopedia of Genes and Genomes pathways were triggered, in which neuroactive ligand–receptor interactions scored the least false discovery rate. Also, huperzine A was predicted to modulate 54 cellular components, 120 molecular functions, and 873 biological processes. Furthermore, huperzine A possessed a binding affinity of −8.7 kcal/mol with AChE and interacted within the active site of AChE via H-bonds and hydrophobic interactions.

Highlights

Alzheimer’s disease (AD) is one of the neurodegenerative pathogeneses that majorly affect geriatric subjects, characterized by increased confusion and impaired cognitive function, and difficulty in learning and organizing thoughts (Bondi et al, 2017)
A total of 100 different proteins were predicted as targets of huperzine A, of which 42 were identified to be regulated at a minimum probability of 0.05 in which AChE was considered to be primarily targeted with the probability of 1
The huperzine A-regulated targets were under seven different categories, i.e., hydrolase, kinase, protease, family A G protein-coupled receptor, ligand-gated ion channel, electrochemical transporter, and enzyme

Summary

Introduction

Alzheimer’s disease (AD) is one of the neurodegenerative pathogeneses that majorly affect geriatric subjects, characterized by increased confusion and impaired cognitive function, and difficulty in learning and organizing thoughts (Bondi et al, 2017). AD pathogenesis has been categorized as polygenic (Bird, 2008) due to the involvement of multiple genes in its progression. Donepezil is associated with multiple side effects like nausea, vomiting, weight loss, frequent urination, and muscle cramps. Other anti-Alzheimer’s drugs like N-methyl-D-aspartate antagonists, nicotine receptor agonists, peroxisome proliferator-activated receptor-γ agonists, and 5hydroxytryptamine modulators are linked with multiple side effects (Casey et al, 2010). This underlines the necessity of identifying new therapeutic agents for the pharmacotherapy of AD

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