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In Silico Evaluation of Hexamethylene Amiloride Derivatives as Potential Luminal Inhibitors of SARS-CoV-2 E Protein Jalily, Pouria H.; Jalily Hasani, Horia; Fedida, David

Abstract

The coronavirus E proteins are small membrane proteins found in the virus envelope of alpha and beta coronaviruses that have a high degree of overlap in their biochemical and functional properties despite minor sequence variations. The SARS-CoV-2 E is a 75-amino acid transmembrane protein capable of acting as an ion channel when assembled in a pentameric fashion. Various studies have found that hexamethylene amiloride (HMA) can inhibit the ion channel activity of the E protein in bilayers and also inhibit viral replication in cultured cells. Here, we use the available structural data in conjunction with homology modelling to build a comprehensive model of the E protein to assess potential binding sites and molecular interactions of HMA derivatives. Furthermore, we employed an iterative cycle of molecular modelling, extensive docking simulations, molecular dynamics and leveraging steered molecular dynamics to better understand the pore characteristics and quantify the affinity of the bound ligands. Results from this work highlight the potential of acylguanidines as blockers of the E protein and guide the development of subsequent small molecule inhibitors.

Item Metadata

Title
In Silico Evaluation of Hexamethylene Amiloride Derivatives as Potential Luminal Inhibitors of SARS-CoV-2 E Protein
Creator
Jalily, Pouria H.; Jalily Hasani, Horia; Fedida, David
Publisher
Multidisciplinary Digital Publishing Institute
Date Issued
2022-09-13
Description
The coronavirus E proteins are small membrane proteins found in the virus envelope of alpha and beta coronaviruses that have a high degree of overlap in their biochemical and functional properties despite minor sequence variations. The SARS-CoV-2 E is a 75-amino acid transmembrane protein capable of acting as an ion channel when assembled in a pentameric fashion. Various studies have found that hexamethylene amiloride (HMA) can inhibit the ion channel activity of the E protein in bilayers and also inhibit viral replication in cultured cells. Here, we use the available structural data in conjunction with homology modelling to build a comprehensive model of the E protein to assess potential binding sites and molecular interactions of HMA derivatives. Furthermore, we employed an iterative cycle of molecular modelling, extensive docking simulations, molecular dynamics and leveraging steered molecular dynamics to better understand the pore characteristics and quantify the affinity of the bound ligands. Results from this work highlight the potential of acylguanidines as blockers of the E protein and guide the development of subsequent small molecule inhibitors.
Subject
SARS-CoV-2; envelop protein; hexamethylene amiloride derivatives; viroporins; steered molecular dynamics; molecular docking
Genre
Article
Type
Text
Language
eng
Date Available
2023-07-24
Provider
Vancouver : University of British Columbia Library
Rights
CC BY 4.0
DOI
10.14288/1.0434266
URI
http://hdl.handle.net/2429/85297
Affiliation
Medicine, Faculty of; Anesthesiology, Pharmacology and Therapeutics, Department of
Citation
Jalily, P.H.; Jalily Hasani, H.; Fedida, D. In Silico Evaluation of Hexamethylene Amiloride Derivatives as Potential Luminal Inhibitors of SARS-CoV-2 E Protein. Int. J. Mol. Sci. 2022, 23, 10647
Publisher DOI
10.3390/ijms231810647
Peer Review Status
Reviewed
Scholarly Level
Faculty; Graduate
Rights URI
https://creativecommons.org/licenses/by/4.0/
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CC BY 4.0