Computational drug repurposing strategy predicted peptide-based drugs that can potentially inhibit the interaction of SARS-CoV-2 spike protein with its target (humanACE2).

Samuel Egieyeh,Burtram Fielding,Alan Christofells,Sarel Malan,Elizabeth Egieyeh,Israel Silman

doi:10.1371/journal.pone.0245258

Samuel Egieyeh, Burtram Fielding + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0245258

Copy DOI

Abstract

Drug repurposing for COVID-19 has several potential benefits including shorter development time, reduced costs and regulatory support for faster time to market for treatment that can alleviate the current pandemic. The current study used molecular docking, molecular dynamics and protein-protein interaction simulations to predict drugs from the Drug Bank that can bind to the SARS-CoV-2 spike protein interacting surface on the human angiotensin-converting enzyme 2 (hACE2) receptor. The study predicted a number of peptide-based drugs, including Sar9 Met (O2)11-Substance P and BV2, that might bind sufficiently to the hACE2 receptor to modulate the protein-protein interaction required for infection by the SARS-CoV-2 virus. Such drugs could be validated in vitro or in vivo as potential inhibitors of the interaction of SARS-CoV-2 spike protein with the human angiotensin-converting enzyme 2 (hACE2) in the airway. Exploration of the proposed and current pharmacological indications of the peptide drugs predicted as potential inhibitors of the interaction between the spike protein and hACE2 receptor revealed that some of the predicted peptide drugs have been investigated for the treatment of acute respiratory distress syndrome (ARDS), viral infection, inflammation and angioedema, and to stimulate the immune system, and potentiate antiviral agents against influenza virus. Furthermore, these predicted drug hits may be used as a basis to design new peptide or peptidomimetic drugs with better affinity and specificity for the hACE2 receptor that may prevent interaction between SARS-CoV-2 spike protein and hACE2 that is prerequisite to the infection by the SARS-CoV-2 virus.

Highlights

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, known as nCOV-2019), a virus that recently emerged as a human pathogen in the city of Wuhan in China’s Hubei province, causes fever, severe respiratory illness, and pneumonia [1]
From the top 1070 drugs docked against the interacting surface of the human angiotensin-converting enzyme 2 (hACE2) receptor, we described two peptide drugs with good predicted binding affinity and poses that might disrupt the protein-protein interactions between the SARS-CoV-2 spike protein and the hACE2 receptor
We conducted a molecular dynamics simulation on the crystal structure downloaded from the protein data bank, i.e. the SARS-CoV-2 spike protein-hACE2 complex, before separating hACE2 receptor from the complex for the molecular docking study

Summary

Introduction

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, known as nCOV-2019), a virus that recently emerged as a human pathogen in the city of Wuhan in China’s Hubei province, causes fever, severe respiratory illness, and pneumonia [1]. Many drugs and therapeutics, including hydroxychloroquine, azithromycin [5], remdesivir [6], and idasanutlin [7], are currently being tested or suggested, no effective prophylactics or therapeutics have yet been identified. This underscores the urgency to find the much needed intervention for this global pandemic

Objectives

Methods

Results

Conclusion