Computational Evidences of Phytochemical Mediated Disruption of PLpro Driven Replication of SARS-CoV-2: A Therapeutic Approach against COVID-19

Curr Pharm Biotechnol. 2021;22(10):1350-1359. doi: 10.2174/1389201021999201110204116.


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.

Keywords: COVID-19; MD simulation; RMSD; SARS-CoV-2; electrostatic interaction.; molecular docking.

MeSH terms

  • COVID-19*
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Papain
  • Peptide Hydrolases
  • Phytochemicals
  • SARS-CoV-2*


  • Phytochemicals
  • Peptide Hydrolases
  • Papain