Target-based drug discovery, ADMET profiling and bioactivity studies of antibiotics as potential inhibitors of SARS-CoV-2 main protease (Mpro).

Adewusi John Adepoju,Victoria Adeola Falade,Sabitu Babatunde Olasupo,Ibrahim Olaide Adedotun,Modinat Wuraola Akinboade,Misbaudeen Abdul-Hammed

doi:10.1007/s13337-021-00717-z

Adewusi John Adepoju, Victoria Adeola Falade + Show 4 more

Open Access

https://doi.org/10.1007/s13337-021-00717-z

Copy DOI

Abstract

A recent outbreak of a new strain of Coronavirus (SARS-CoV-2) has become a global health burden, which has resulted in deaths. No proven drug has been found to effectively cure this fast-spreading infection, hence the need to explore old drugs with the known profile in tackling this pandemic. A computer-aided drug design approach involving virtual screening was used to obtain the binding scores and inhibiting efficiencies of previously known antibiotics against SARS-CoV-2 main protease (Mpro). The drug-likeness analysis of the repurposed drugs were done using the Molinspiration chemoinformatics tool, while the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis was carried out using ADMET SAR-2 webserver. Other analyses performed include bioactivities of the repurposed drug as a probable anti-SARS-CoV-2 agent and oral bioavailability analyses among others. The results were compared with those of drugs currently involved in clinical trials in the ongoing pandemic. Although antibiotics have been speculated to be of no use in the treatment of viral infections, literature has emerged lately to reveal the antiviral potential and immune-boosting ability of antibiotics. This study identified Tarivid and Ciprofloxacin with binding affinities of − 8.3 kcal/mol and − 8.1 kcal/mol, respectively as significant inhibitors of SARS-CoV-2 (Mpro) with better pharmacokinetics, drug-likeness and oral bioavailability, bioactivity properties, ADMET properties and inhibitory strength compared to Remdesivir (− 7.6 kcal/mol) and Azithromycin (− 6.3 kcal/mol). These observations will provide insight for further research (clinical trial) in the cure and management of COVID-19.

Highlights

The outbreak of a respiratory tract infection identified in a cluster of pneumonia patients in Wuhan China has become a global health challenge that cut across all continents of the world [10]
Sixteen commercial antibiotics were used as ligands, while two clinically drugs (Remdesivir and Azithromycin) whose randomized clinical trials as probable inhibitors of SARS-CoV-2 main protease have been established were used as standards
The structure of SARS-CoV-2 main protease (PDB ID: 6LU7) is shown in Table 1. 6LU7 is a 306 amino acid protease complexed with a native inhibitor N3 (N3-(N-[(5Methylisoxazol-3-Yl) Carbonyl] Alanyl-L-Valyl-N*1*((1r, 2z)-4-(Benzyloxy)-4-Oxo-1-{[(3r)-2-Oxopyrrolidin3-Yl] Methyl} But-2-Enyl)-L-Leucinamide)

Summary

Introduction

The outbreak of a respiratory tract infection identified in a cluster of pneumonia patients in Wuhan China has become a global health challenge that cut across all continents of the world [10]. The present study is aimed at investigating the inhibitory potential of some selected antibiotics against the novel SARS-CoV-2 main protease (Mpro) via target-based drug discovery approach (virtual screening), drug-likeness analysis, oral-bioavailability studies, ADMET profiling, and bioactivity studies.

Results

Conclusion