<p>The Severe Acute Respiratory Syndrome 2
(SARS-CoV-2) is an infectious virus that causes mild to severe life-threatening
upper respiratory tract infection. The virus emerged in Wuhan, China in 2019,
and later spread across the globe. Its genome has been completely sequenced and
based on the genomic information, the virus possessed 3C-Like Main Protease
(3CLpro), an essential multifunctional enzyme that plays a vital role in the
replication and transcription of the virus by cleaving polyprotein at eleven various
sites to produce different non-structural proteins. This makes the protein an important
target for drug design and discovery. Herein, we analyzed the interaction
between the 3CLpro and potential inhibitory compounds identified from the
extracts of <i>Zingiber offinale</i> and <i>Anacardium occidentale</i> using in silico docking
and Molecular Dynamics (MD) Simulation. The crystal structure of SARS-CoV-2
main
protease in complex with 02J (5-Methylisoxazole-3-carboxylic acid) and PEJ
(composite ligand) (PDB Code: 6LU7,2.16Å) retrieved from Protein Data Bank (PDB) and
subject to structure optimization and energy minimization. A total of twenty-nine compounds were obtained
from the extracts of <i>Zingiber
offinale </i>and the leaves of <i>Anacardium occidentale. </i>These compounds were screened for
physicochemical (Lipinski rule of five, Veber rule, and Egan filter), <i>Pan</i>-Assay Interference Structure (PAINS),
and pharmacokinetic properties
to determine the Pharmaceutical Active Ingredients (PAIs). Of the 29 compounds,
only nineteen (19) possessed drug-likeness properties with efficient oral
bioavailability and less toxicity. These compounds subjected to molecular
docking analysis to determine their binding energies with the 3CLpro. The
result of the analysis indicated that the free binding energies of the
compounds ranged between ˗5.08 and -10.24kcal/mol, better than the binding
energies of 02j (-4.10kcal/mol) and PJE (-5.07kcal.mol). Six compounds (CID_99615
= -10.24kcal/mol, CID_3981360 = 9.75kcal/mol, CID_9910474 = -9.14kcal/mol, CID_11697907 = -9.10kcal/mol,
CID_10503282 = -9.09kcal/mol and CID_620012 = -8.53kcal/mol) with good binding
energies further selected and subjected to MD Simulation to determine the stability
of the protein-ligand complex. The results of the analysis indicated that all
the ligands form stable complexes with the protein, although, CID_9910474 and
CID_10503282 had a better stability when compared to other selected
phytochemicals (CID_99615, CID_3981360, CID_620012, and CID_11697907). </p>
Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease
