Background: COVID-19 caused by SARS-CoV-2 has been declared as a global pandemic
by WHO. Comprehensive analysis of this unprecedented outbreak may help to fight against the disease
and may play a pivotal role in decreasing the mortality rate linked with it. Papain-like protease
(PLpro), a multifunctional polyprotein, facilitates the replication of SARS-CoV-2 and evades it from
the host immunological response by antagonizing cytokines, interferons and may be considered as a
potential drug target to combat the current pandemic.
Methods: Natural moieties obtained from medicinal plants were analysed for their potency to target
PLpro of SARS-CoV-2 by molecular docking study and were compared with synthetic analogs named
as remdesivir, chloroquine and favipiravir. The stability of complexes of top hits was analysed by MD
Simulation, and interaction energy was calculated. Furthermore, average RMSD values were computed
and deepsite ligand-binding pockets were predicted using Play Molecule. Drug-like-abilities of these
moieties were determined using ADMET and bond distance between the ligand and active site was assessed
to predict the strength of the interaction.
Results: Nimbocinol (-7.6 Kcal/mol) and sage (-7.3 Kcal/mol) exhibited maximum BA against PLpro
SARS-CoV-2 as evident from molecular docking study, which was found to be even better than
remdesivir (-6.1 Kcal/mol), chloroquine (-5.3 Kcal/mol) and favipiravir (-5.7 Kcal/mol). Both nimbocinol-
PLpro and sage-PLpro SARS-CoV-2 complex exhibited stable conformation during MD Simulation
of 101ns at 310 K, and potential, kinetic and electrostatic interaction energies were computed,
which was observed to be concordant with results of molecular docking study. RMSD average values
were found to be 0.496 ± 0.015 Å and 0.598 ± 0.023 Å for nimbocinol and sage, respectively, thus revealing
that both the deviation and fluctuations during MD Simulation were observed to be least.
Deepsite prediction disclosed that both compounds occupied cryptic pockets in receptor and non-bond
distance analysis revealed the formation of hydrogen bonds during ligand-receptor interaction. ADMET
exploration further validated the drug-like properties of these compounds.
Conclusion: Present study revealed that active constituents of Azadirachta indica and Salvia officinalis
can be potentially used to target SARS-CoV-2 by hindering its replication process.