Background: In December 2019, an outbreak of a pneumonia-like illness, Coronavirusdisease-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 and nelflinavir.
Methods: Natural compound libraries were screened for potential scaffold against MPRO main protease. Molecular dynamics simulation, MM-GBSA and principle 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 O-glycosidic form performing better than corresponding aglyconic form. Simulation studies indicated that glycosidic form of flavonoid as 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 compound. Interestingly, rutin was reported to have inhibitory activity against similar protease (3Cprotease of enterovirus A71) as well as implicated in lung fibrosis.
Conclusion: The present study displaying 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.