Re-purposing of hepatitis C virus FDA approved direct acting antivirals as potential SARS-CoV-2 protease inhibitors

Reaz Uddin; Khurshid Jalal; Kanwal Khan; Zaheer Ul-Haq

doi:10.1016/j.molstruc.2021.131920

Re-purposing of hepatitis C virus FDA approved direct acting antivirals as potential SARS-CoV-2 protease inhibitors

J Mol Struct. 2022 Feb 15:1250:131920. doi: 10.1016/j.molstruc.2021.131920. Epub 2021 Nov 19.

Authors

Reaz Uddin¹, Khurshid Jalal², Kanwal Khan¹, Zaheer Ul-Haq¹

Affiliations

¹ Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Lab 103 PCMD ext., Karachi 75270, Pakistan.
² H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Pakistan.

Abstract

A new coronavirus strain called as SARS-CoV-2 has emerged from Wuhan, China in late 2019 and it caused a worldwide pandemic in a few months. After the Second World War, it is the biggest calamity observed as there is no specific US Food and Drugs Administration (USFDA) approved drug or vaccine available globally for the treatment. Several clinical trials are ongoing for therapeutic alternatives, however with little success rate. Considering that the time is crucial, the drug repurposing and data obtained from in silico models are one of the most important approaches to identify possible lead inhibitors against SARS-CoV-2. More recently, the Direct Acting Antivirals (DAAs) are emerged as the most promising drugs to control viral infection. The Main Protease (Mpro), a key enzyme in the SARS-CoV-2 replication cycle, is found close homolog to the Hepatitis C Virus (HCV) protease and could be susceptible of blocking its activity by DAAs. In the current study, the DAAs were investigated as antivirals using structure based computational approach against Mpro of SARS-CoV-2 to propose them as new therapeutics. In total, 20 DAAs of HCV, including a reference compound O6K were docked against Mpro. The docked structures were examined and resulted in the identification of six highly promising DAAs i.e. beclabuvir, elbasvir, paritaprevir, grazoprevir, simeprevir, and asunapevir exhibiting high theoretical binding affinity to Mpro from SARS-CoV-2 in comparison to other DAAs. Furthermore, the post docking analysis revealed that Cys145, Glu166, His163, Thr26, His41, and Met165 played potential role for the binding of these DAAs inside binding site of Mpro. Furthermore, the correlation between binding energies were found in accord with the results from the reported IC₅₀s for some DAAs. Overall, the current study provides insight to combat COVID-19 using FDA-approved DAAs as repurposed drugs.

Keywords: Direct Acting Antivirals (DAAs); Drug re-purposing; Hepatitis C Virus; Mpro protease; Protease inhibitors; SARS-CoV-2.