A structural-based virtual screening and in vitro validation reveals novel effective inhibitors for SARS-CoV-2 helicase and endoribonuclease

Researchers worldwide are looking for molecules that might disrupt the COVID-19 life cycle. Endoribonuclease, which is responsible for processing viral RNA to avoid detection by the host defense system, and helicase, which is responsible for unwinding the RNA helices for replication, are two key non...

Full description

Saved in:
Bibliographic Details
Published in:Journal of biomolecular structure & dynamics 2023-08, p.1-14
Main Authors: Ibrahim, Ibrahim M., Elfiky, Abdo A., Mahmoud, Sara H., ElHefnawi, Mahmoud
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Researchers worldwide are looking for molecules that might disrupt the COVID-19 life cycle. Endoribonuclease, which is responsible for processing viral RNA to avoid detection by the host defense system, and helicase, which is responsible for unwinding the RNA helices for replication, are two key non-structural proteins. This study performs a hierarchical structure-based virtual screening approach for NSP15 and helicase to reach compounds with high binding probabilities. In this investigation, we incorporated a variety of filtering strategies for predicting compound interactions. First, we evaluated 756,275 chemicals from four databases using a deep learning method (NCI, Drug Bank, Maybridge, and COCONUT). Following that, two docking techniques (extra precision and induced fit) were utilized to evaluate the compounds' binding affinity, followed by molecular dynamic simulation supported by the MM-GBSA free binding energy calculation. Remarkably, two compounds (90616 and CNP0111740) exhibited high binding affinity values of -66.03 and -12.34 kcal/mol for helicase and NSP15, respectively. The VERO-E6 cell line was employed to test their in vitro therapeutic impact. The CC50 for CNP0111740 and 90616 were determined to be 102.767 μg/ml and 379.526 μg/ml, while the IC50 values were 140.176 μg/ml and 5.147 μg/ml, respectively. As a result, the selectivity index for CNP0111740 and 90616 is 0.73 and 73.73, respectively. Finally, these compounds were found to be novel, effective inhibitors for the virus; however, further in vivo validation is needed.Communicated by Ramaswamy H. Sarma.
ISSN:0739-1102
1538-0254
DOI:10.1080/07391102.2023.2250479