In silico prediction of potential inhibitors for SARS-CoV-2 Omicron variant using molecular docking and dynamics simulation-based drug repurposing

by Selleckchem | Mar 13 2023

Background: In November 2021, variant B.1.1.529 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified by the World Health Organization (WHO) and designated Omicron. Omicron is characterized by a high number of mutations, thirty-two in total, making it more transmissible than the original virus. More than half of those mutations were found in the receptor-binding domain (RBD) that directly interacts with human angiotensin-converting enzyme 2 (ACE2). This study aimed to discover potent drugs against Omicron, which were previously repurposed for coronavirus disease 2019 (COVID-19). All repurposed anti-COVID-19 drugs were compiled from previous studies and tested against the RBD of SARS-CoV-2 Omicron.

Methods: As a preliminary step, a molecular docking study was performed to investigate the potency of seventy-one compounds from four classes of inhibitors. The molecular characteristics of the best-performing five compounds were predicted by estimating the drug-likeness and drug score. Molecular dynamics simulations (MD) over 100 ns were performed to inspect the relative stability of the best compound within the Omicron receptor-binding site.

Results: The current findings point out the crucial roles of Q493R, G496S, Q498R, N501Y, and Y505H in the RBD region of SARS-CoV-2 Omicron. Raltegravir, hesperidin, pyronaridine, and difloxacin achieved the highest drug scores compared with the other compounds in the four classes, with values of 81%, 57%, 18%, and 71%, respectively. The calculated results showed that raltegravir and hesperidin had high binding affinities and stabilities to Omicron with ΔGbinding of - 75.7304 ± 0.98324 and - 42.693536 ± 0.979056 kJ/mol, respectively. Further clinical studies should be performed for the two best compounds from this study.

Comments：

What was the objective of the study?
The objective of the study was to identify potential drugs against the Omicron variant of SARS-CoV-2 by testing previously repurposed anti-COVID-19 drugs against the receptor-binding domain (RBD) of SARS-CoV-2 Omicron.

What methods were used in the study?
The study first performed a molecular docking study to investigate the potency of 71 compounds from four classes of inhibitors. The molecular characteristics of the best-performing five compounds were then predicted by estimating drug-likeness and drug score. Finally, molecular dynamics simulations were performed to inspect the relative stability of the best compound within the Omicron receptor-binding site.

What were the results of the study?
The study identified the crucial roles of five mutations in the RBD region of SARS-CoV-2 Omicron. Raltegravir, hesperidin, pyronaridine, and difloxacin achieved the highest drug scores compared with the other compounds in the four classes. Raltegravir and hesperidin had high binding affinities and stabilities to Omicron with ΔGbinding of -75.7304 ± 0.98324 and -42.693536 ± 0.979056 kJ/mol, respectively.

What are the implications of the study?
The study suggests that raltegravir and hesperidin may be potential drugs against the Omicron variant of SARS-CoV-2. However, further clinical studies should be performed to confirm their efficacy and safety.