Title:Computational Investigation of Natural Substances as SARS-CoV-2 Main Protease Inhibitors: A Virtual Screening Method
Volume: 21
Issue: 1
Author(s): Deepak K. Lokwani*, Sangita R. Chavan, Shirish P. Jain, Samiksha R. Shengokar and Titiksh L. Devale
Affiliation:
- Department of Pharmaceutical Chemistry, Rajarshi Shahu College of Pharmacy, Buldhana, Maharashtra, 443001, India
Keywords:
COVID-19, Mpro inhibitor, ZINC database, molecular docking, MD simulations, MMGBSA.
Abstract:
Introduction: The coronavirus disease 2019 (COVID-19) pandemic, caused the
by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a profound
impact on public health, overburdening healthcare systems, and disrupting global economies.
Moreover, the absence of specific antiviral drugs remains a major challenge in
COVID-19 treatment. The SARS-CoV-2 main protease (Mpro) is a crucial therapeutic
target due to its essential role in viral replication. The objective of this study was to identify
natural compounds with potential inhibitory activity against SARS-CoV-2 Mpro, which
could be used alone or in combination with repositioned drugs for the treatment of
COVID-19.
Methods: A total of 224,205 natural compounds from the ZINC database were virtually
screened against SARS-CoV-2 Mpro using a sequential molecular docking protocol with
increasing levels of exhaustiveness. The top 88 compounds were further evaluated using
MM-GBSA calculations to determine their binding free energies. Molecular dynamics
(MD) simulations (100 ns) were conducted for the top four compounds to assess complex
stability and ligand interactions. Structural stability and protein-ligand interactions were
assessed using various statistical parameters. Post-MD binding free energy calculations
were also performed.
Results: Four compounds, ZINC000085626103, ZINC000085625768, ZINC000085488571,
and ZINC000085569275, were identified based on their docking scores (ranging from -
11.876 to -12.682 kcal/mol) and MM-GBSA binding energies (ranging from -50.11 to -
64.8 kcal/mol). All these compounds formed stable complexes with Mpro during MD simulations,
with ZINC000085488571 exhibiting the lowest protein RMSD (0.15 ± 0.02 nm)
and RMSF (0.10 ± 0.04 nm). These compounds interacted with key active site residues and
maintained stable hydrogen bonding and compact structures throughout the simulation.
Post-simulation binding free energy values ranged from -38.29 to -18.07 kcal/mol, further
indicating strong and stable binding affinities.
Discussion: The in silico screening results confirmed the strong binding affinity and structural
stability of the selected natural compounds at the SARS-CoV-2 Mpro active site. The
MD simulation results further highlighted consistent engagement with catalytically relevant
residues, indicating their potential for inhibitory activity.
Conclusion: This study identifies four natural compounds with strong binding affinity and
structural stability against SARS-CoV-2 Mpro, supporting their candidacy for further investigation
as potential antiviral agents for COVID-19 treatment.
