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In silico characterization of bioactive phytochemicals as antivirals targeting the reovirus σ1 protein for inhibiting

Eitu Dey^1,2, Shipon Dey^1,2, Leu Nandi^1,2

¹Department of Biochemistry and Biotechnology, University of Science and Technology Chittagong (USTC), Chattogram, Chittagong, Bangladesh.

|June 3, 2026

Abstract:

Mammalian orthoreoviruses (MRVs), commonly known as reoviruses, are an emerging zoonotic threat that are known for their broad host tropism and potential for causing severe clinical pathology in both humans and animals. Despite this epidemic risk, currently, there are no approved therapeutic agents that are able to disrupt MRV transmission. The viral attachment protein sigma1 (σ1), mediating the entry of the virus into the host cells is a critical target for antiviral intervention. This study used an in silico structure-based drug design strategy to screen for bioactive phytochemicals that are capable of inhibiting the function of σ1. We screened a library of 376 bioactive phytochemicals with known antiviral potential against the σ1 receptor binding domain using molecular docking. Among the candidates, catechin gallate was the most potent inhibitor, possessing a superior binding affinity of -8.1 kcal/mol followed by bilobetin, which also showed a favorable binding affinity of -7.8 kcal/mol. Structural interaction analysis showed that catechin gallate and bilobetin occupies the active JAM-A binding pocket, forming stable interactions with some of the residues, including Gly381, Glu384, and Arg316, which are essential for the reovirus in the cellular attachment process. Subsequent pharmacokinetic and toxicity profiling proved that catechin gallate possessed favorable safety and drug-like characteristics, whereas bilobetin exhibited an unfavorable toxicity profile. In addition, molecular dynamics (MD) simulations supported the stability of σ1-catechin gallate complex relative to the σ1-bilobetin complex. Extensive post-trajectory analyses including RMSD, RMSF, Rg, SASA, and H-bond, showed that the binding of the catechin gallate significantly increases the rigidity and compactness of the protein. PCA indicated that the first three principal components (PC1-PC3) accounted for 74.1% and 76.2% of the total variance for catechin gallate and bilobetin, respectively, with the σ1-catechin gallate complex displaying a more compact conformational cluster consistent with greater stability. MM-GBSA analysis also showed favorable binding for both complexes, with estimated binding energies of -15.6097 ± 3.21 kcal/mol and -13.7327 ± 5.44 kcal/mol for the σ1-catechin gallate and σ1-bilobetin complexes, respectively, with catechin gallate showing comparatively stronger binding. Our results reveal a precise mechanism by which the lead compound catechin gallate sterically occludes the σ1 receptor-binding pocket, thereby likely abrogating viral attachment to the host cell. This comprehensive preclinical evaluation provides supporting evidence for the further development of catechin gallate using in vivo models and clinical trials as a promising antiviral candidate against reovirus infection.

Insights

This study identified catechin gallate as a promising antiviral compound against mammalian orthoreoviruses (MRVs). Molecular docking and simulations show it effectively inhibits viral attachment by blocking the sigma1 protein, offering a potential new treatment for reovirus infections.

Area of Science:

Virology
Drug Discovery
Computational Chemistry

Background:

Mammalian orthoreoviruses (MRVs) pose an emerging zoonotic threat with no approved therapeutics to prevent transmission.
The viral attachment protein sigma1 (σ1) is a key target for antiviral interventions due to its role in host cell entry.

Purpose of the Study:

To identify bioactive phytochemicals that inhibit MRV sigma1 (σ1) protein function using in silico drug design.
To evaluate the potential of identified compounds as antiviral agents against reovirus infection.

Main Methods:

Screening of 376 phytochemicals against the σ1 receptor binding domain using molecular docking.
Pharmacokinetic and toxicity profiling, molecular dynamics (MD) simulations, and binding energy analysis (MM-GBSA).

Main Results:

Catechin gallate showed the highest binding affinity (-8.1 kcal/mol) and occupied the JAM-A binding pocket of σ1.
Molecular dynamics simulations confirmed the stability of the σ1-catechin gallate complex, indicating enhanced protein rigidity.
Catechin gallate demonstrated favorable pharmacokinetic and safety profiles, unlike bilobetin.

Conclusions:

Catechin gallate effectively inhibits reovirus attachment by sterically blocking the σ1 receptor-binding pocket.
This study provides preclinical evidence supporting catechin gallate as a potential antiviral candidate for reovirus infections, warranting further in vivo and clinical investigation.

Read full analysis

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