Study examines phytochemical-based antivirals against SARS-CoV-2 infection


A recent article on the research place* Preprint server demonstrated biologically active plant-based antiviral agents effective against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection.

To learn: Identification of plant-based drug-like molecules as potential inhibitors against hACE2 and S-RBD of SARS-CoV-2 using a multilevel molecular docking and dynamic simulation approach. Credit: Design_Cells/Shutterstock


The development of antiviral agents with significant efficacy against the later emerging SARS-CoV-2 strains is of paramount importance to protect global public health during the ongoing Coronavirus Disease 2019 (COVID-19) pandemic.

Plant-based phytochemicals, or bioactive compounds, exhibit potential immunomodulatory and therapeutic effects against multiple SARS-CoV-2 targets. Also, plant-based bioactive molecules have an intrinsic broad spectrum of biological abilities such as antiviral, antioxidant and anti-inflammatory abilities with little or no side effects.

SARS-COV-2 infection in humans begins after recognition and attachment of the viral spike protein (S) receptor-binding domain (RBD) to human angiotensin-converting enzyme 2 (hACE2) receptors on the host cell surface. In addition, the number of ACE2-binding residues in SARS-CoV-2 is higher than in SARS-CoV due to significant mutations, particularly in its RBDs. Therefore, organs such as the heart, respiratory system, liver, kidneys and intestines are at high risk of SARS-CoV-2 infection.

A better understanding of the underlying interaction pathways between SARS-CoV-2 and host cell receptors that impede virus-cell junction is a potential strategy for COVID-19 management.

About the study

In the present study, the researchers led an in silico Analysis of approximately 1000 phytochemicals against two SARS-CoV-2 targets, i.e. hACE2 receptors and viral RBD protein, using a multi-level molecular docking technique. To calculate the binding force, SMD (Steered Molecular Dynamics) simulations of the five best compounds derived using the Glide Xtra Precision (Glide-XP) docking score were performed.

Several criteria such as B. drug likelihood; Analysis of Absorption, Distribution, Metabolism, Elimination and Toxicity (ADMET); pharmacokinetics; pharmacodynamics; inhibition constant (pKi); Ligand Efficiency (LE); the probability of being active (Pa); and the probability of being inactive (Pi) were considered to achieve the highest efficacy of the therapeutic target with no or minimal side effects.

The descriptors such as drug likelihood, molecular weight, hydrogen (H) bond donor/acceptor, AlogP, polar surface, rotatable bonds, colorectal adenocarcinoma 2 (Caco2) cells, human intestinal absorption, human oral bioavailability, blood-brain barrier, Plasma protein binding, Ames mutagenesis, number of oxygen and nitrogen atoms, and water solubility were predicted for the compounds.

These steps led to the identification of the three best ligands with superior work and potency. Subsequently, the hit molecules were subjected to 100 ns molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface (MM-PBSA) binding energy assessments.


The study results revealed five promising phytochemicals for both the SARS-CoV-2 RBD protein and the hACE2 receptors: ascorbic acid, palasitrin, isoorientin and rosavin, and eriocitrin for ACE2; and procyanidin C1, cinnamannin B1, tannic acid, terflavin A, and isoskimmiwallin for the SARS-CoV-2 RBD protein.

The five compounds showed significant ability to bind to the receptor binding region of the targets with high binding energy, significant docking scores and close contacts, and serve as a potential inhibitor of SAR-CoV-2 infection by blocking the interaction of the ACE2 receptor and viral RBD.

Additional analysis led to the identification of the top three hits for both targets: palasitrin, rosavin, isoorientin; and isoskimmiwallin, terflavin A, cinnamonin B1 for ACE2 and RBD, respectively. The free energy of binding of the identified hit compounds for ACE2 and RBD ranged from -9.01 to -11.982 kcal/mol and -7.782 to -8.51 kcal/mol, respectively.

At the ACE2 receptor, isoorientin showed the highest force and internal work scores, rosavin the second highest force score, and palasitrin the second highest work score. Additionally, against the SARS-CoV-2 RBD protein, IsoSkimmiwallin had the highest work and second-highest power scores, Terflavin A second-highest work, and cinnamonnine the highest power scores. The Pa and Pi values ​​of the lead compounds varied between 0.093 and 0.725 when Pi was less than Pa, indicating their better drug capability against both SARS-CoV-2 targets.


The study results revealed five potent phytocompounds against the SARS-CoV-2 RBD protein and hACE2 receptors. In addition, additional assessments, including drug likelihood analyses, identified three lead compounds for the RBD (terflavin A, isoskimmiwallin, cinnamonnin B1) and ACE2 (palasitrin, isoorientin, rosavin) targets. The three hit compounds were non-toxic and showed better pharmacokinetics and good inhibitory capacity under physiological conditions. As a result, the phytocompounds could be potential antiviral drugs against COVID-19.

The authors stated that before considering the phytomolecules as therapeutic interventions for SARS-CoV-2 infection, they should be optimized pre-clinically in vitro or in vivo experimental trials are required.

Overall, the present work provided solid evidence for the antiviral therapeutic efficacy of plant-based bioactive compounds that disrupt the contact between SARS-CoV-2 and the host cell and hence can be used to treat and treat COVID-19.

*Important NOTE

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


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