In Silico Analysis of Off-Target Effects of Ivermectin Drug

Simran Walia and Poonam Sharma

Department of Zoology, Gargi College, University of Delhi, Delhi, India

Corresponding Author E-mail: poonam.sharma@gargi.du.ac.in

DOI : http://dx.doi.org/10.13005/bbra/2970

ABSTRACT:

Researchers all across the world are repurposing medications to fight the coronavirus, but they come with a plethora of negative side effects. Ivermectin, a common repurposed medicine, binds to the importin protein in Covid-19 patients and suppresses viral replication. Ivermectin also binds to pentameric ligand-gated ion channels, increasing cell membrane ion permeability and triggering cell hyperpolarization.  In this study, in silico analysis of non-target proteins of ivermectin and protein interactions was performed to better understand its off-target effects on other biological processes. Detailed information on the drug, its target and non-target proteins, their properties, protein-protein interactions, and pathways involved was analysed using databases such as DrugBank, NCBI Gene Database, BLAST, UCSC Gene Sorter, GeneMANIA, STRING, Kyoto Encyclopaedia of Genes and Genomes (KEGG) Pathway Database, and Reactome. Due to structural similarities and protein interactions with pentameric ligand-gated ion channels like α1β2γ2L GABA (A) receptors, GLRA-3 receptor, α7 nAChR, P2X4 cation channel, and IMPα/β1, ivermectin was found to bind to non-target protein families, GLR, GABA, nAChR, 5-HT receptors and, P2XR and ZACN, IPO5, RANBP6, TNPO1 and, TNPO2 proteins. These non-target proteins include neurotransmitter-gated ion channels, nuclear receptors, and transporter proteins, and they can interfere with signal transmission and neuroactive ligand-receptor interactions, as well as alter the function of proteins that interact with these target proteins indirectly. Off-target effects of ivermectin can be hypotension, visual hallucinations, loss of coordination and balance, depression, and neurological disorders. These findings highlight the need for a comprehensive evaluation of all repurposing drugs for their off-target effects before public use.

KEYWORDS: Covid-19; Ivermectin; Importin; Glycine receptors; GABA

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