Background: In December 2019, an outbreak of a pneumonia-like illness, Corona virus disease 2019 (COVID-19), originating from Wuhan, China, was linked to novel coronavirus,
now termed SARS-CoV-2. Unfortunately, no effective drugs or vaccines have been reported
yet. The main protease (MPRO) remains the most validated pharmacological target for the design
and discovery of inhibitors.
Objective: The purpose of the study was to find a prospective natural scaffold as an inhibitor for
MPRO main protease in SARS-CoV-2 and compare it with repurposed antiviral drugs lopinavir
Methods: Natural compound libraries were screened for potential scaffold against MPRO main
protease. Molecular dynamics simulation, MM-GBSA and principal component analyses of enzyme-ligand complexes were carried out with the top-ranking hits and compared with the repurposed antiviral drugs lopinavir and nelfinavir.
Results: The structure-based virtual screening indicated phenylbenzopyrone of flavonoids as one
of the top-ranking scaffolds that have the potential to inhibit the main protease with the Oglycosidic form, performing better than the corresponding aglyconic form. Simulation studies
indicated that glycosidic form of flavonoid is a more suitable inhibitor with compounds rutin,
procyanidin B6, baicalin and galloylquercetin, demonstrating high affinity and stability, and rutin, emerging as one of the best candidate compounds. Interestingly, rutin was reported to have
inhibitory activity against similar protease (3Cprotease of enterovirus A71) and implicated in
Conclusion: The present study on flavonoids, possessing a potential scaffold for inhibiting main
protease activity for all betacoronavirus is an attempt to provide new and safe drug leads within a
reasonably short period.