Study shows potential inhibition of SARS-CoV-2 main protease by natural phytochemicals

A recent study posted to the Research Square* preprint server, and currently under consideration at the Journal of Molecular Modeling, assessed the molecular dynamics of potentially active natural phytochemicals to target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro).

Study: Molecular dynamics and docking studies on potentially active natural phytochemicals for targeting SARS-CoV-2 Main Protease. Image Credit: Kateryna Kon/Shutterstock


The morbidity and mortality caused by the coronavirus disease 2019 (COVID-19) pandemic have been significantly curbed by SARS-CoV-2 vaccines. However, there is considerable skepticism regarding vaccine-related health complications post-administration. 

About the study

The present study investigated the effectiveness of phytochemical constituents, present in four medicinal herbs, in neutralizing SARS-CoV-2 Mpro and their mechanism of action.

The team employed the SARS-CoV-2 Mpro receptor that consisted of domains I and II having β-barrels while domain III had α-helices. Docking and visualization were performed on this receptor. Aegle marmelos, Coleus amboinicus, Aerva lanta, and Biophytum sensitivum constituting 20, 24, 17, and 26 phytochemicals, respectively, were used to obtain the phytochemicals.

The study then assessed the drug-likeness of the screened drugs, ensuring that each compound had 500 g/mol or less molecular weight, five or fewer hydrogen donors, less than 10 hydrogen acceptors, less than 10 rotatable bonds, less than 140 polar surface area (PSA), and less than 12 total hydrogen bond donors and acceptors.

Furthermore, the five pharmacokinetic properties, namely absorption, distribution, metabolism, excretion, and toxicity (ADME/T) of the drugs were also evaluated. A quantitative structure-activity relationship (QSAR) was used to calculate the ADME/T properties like aqueous solubility, cytochrome P450 inhibition (CYP250), blood-brain barrier penetration (BBB), hepatotoxicity, plasma protein binding (PPB), and human intestinal absorption.

The team chose the binding site of the Mpro according to the location of peptide inhibitor N3. Also, a hotspot was formed at the interaction site of the polar and nonpolar receptors using high throughput virtual screening (HTVS). Moreover, the binding energies (BEs) of the phytochemicals were calculated and molecular dynamics (MD) simulations of protein-ligand complexes with high docking values were performed.


The study assessed 87 phytochemicals obtained from the four herbs. The binding energy for Aegle Marmelos phytochemicals ranged from −8.55 kcal/mol to -7.14 kcal/mol while the LibDock score ranged between 142.00 and 63.00. Notably, tigogenin, aegelinoside, and dehydromarmeli had the highest binding energies of -8.55 kcal/mol, -8.54 kcal/mol, and -8.53 kcal/mol, respectively.

Also, imperatorin, O-prenylhalfordinol, skimmianine, xanthotoxin, N-[2-ethoxy-2-(4-methoxyphenyl)ethyl]cinnamide, aeglemarmaelosine, aegeline, and anhydromarmeline had binding energies ranging from − 8.41 kcal/mol to -8.06 kcal/mol.

An alpha-glucosidase inhibitor found in Aegle Marmelos called aegelinoside B, interacted with glutamic acid-166 (GLU166), glutamine-192 (GLN192), threonine-190 (THR190), arginine-188 (ARG188), and GLN189.

Out of the 17 phytochemicals present in Aerva lanata, a biologically active canthin-6-one alkaloid, called ervoside, had a LibDock score of 129.69 kcal/mol. Amino acids residues like tyrosine-54 (TYR54), histidine-172 (HIS172), cysteine-145 (CYS145), serine-144 (SER144), methionine-165 (MET165), and MET49 interacted with ervoside.

Another phytochemical called feruloyltyramine had a LibDock score of 123.22 kcal/mol and had three hydrogen bonds with the viral protein. Quercetin, with a LibDock score between 110 to 130 kcal/mol, exhibited protective effects against COVID-19-related kidney injuries as a result of its five hydrogen bonds with glycine-143 (GLY143), SER144, and MET165 amino acid residues.

Epicatechin, present in Biophytum sensitivum, had binding energy of -7.69 kcal/mol. Residues including HIS164, HIS163, SER144, phenylalanine-140 (PHE140), and asparagine-142 (ASN142) interacted with this ligand. Also, all the phytochemicals present in Coleus amboinicus had LibDock scores of less than 100.

All compounds except 3-hydroxy-4-methoxybenzoic acid had sufficient oral bioavailability to function efficiently as potential oral drugs. Either low, medium, high, or very high levels of BBB penetration was observed for most of the drugs except gamma sitosterol, 4′,7-Dimethoxykaempferol, stigmast-4-en-3-one, dl-Phenylephrine, 3-hydroxy-4-methoxybenzoic acid, ervoside, and methoxykaempferol. Also, gamma sitosterol, anhydromarmeline, and stigmast-4-en-3-one showed significant levels of plasma protein binding.


The study findings showed the potency of biochemical phytochemicals obtained from herbs in targeting the SARS-CoV-2 Mpro receptor.

According to this study, six of the active phytochemicals can be further assessed as potential Mpro inhibitors based on their significant docking scores. These efficient phytochemicals are ervoside and feruloyltyramine obtained from Aerva lanata, epicatechin from Biophytum sensitivum, and epoxyaurapten, marmin, and aegelinoside B from Aegle Marmelos.

The researchers believed that these results can form the foundation for further studies of medicinal herbs and their usage as a therapeutic device against SARS-CoV-2.

*Important notice

Research Square publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Sandhya KS, Achuthsankar S. Nair. (2022). Molecular dynamics and docking studies on potentially active natural phytochemicals for targeting SARS-CoV-2 Main Protease. Research Square. doi:

Posted in: Medical Science News | Medical Condition News | Disease/Infection News

Tags: Amino Acid, Arginine, Asparagine, Blood, Brain, Compound, Coronavirus, Coronavirus Disease COVID-19, covid-19, Cysteine, Cytochrome P450, Drugs, Glutamic Acid, Glutamine, Glycine, High Throughput, Histidine, Kidney, Ligand, Metabolism, Methionine, Mortality, Pandemic, Phenylalanine, Phytochemical, Protein, Quercetin, Receptor, Research, Respiratory, SARS, SARS-CoV-2, Serine, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Threonine, Tyrosine, Vaccine

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Bhavana Kunkalikar

Bhavana Kunkalikar is a medical writer based in Goa, India. Her academic background is in Pharmaceutical sciences and she holds a Bachelor's degree in Pharmacy. Her educational background allowed her to foster an interest in anatomical and physiological sciences. Her college project work based on ‘The manifestations and causes of sickle cell anemia’ formed the stepping stone to a life-long fascination with human pathophysiology.

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