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Purpose <p>Human Metapneumovirus (HMPV) and Human Respiratory Syncytial Virus (HRSV) cause severe acute lower respiratory tract infections (ALRTIs), particularly in children, the elderly, and immunocompromised individuals. Despite their clinical significance, effective antiviral therapies remain limited. Both viruses rely on a conserved RNA-dependent RNA polymerase (RdRp) for replication and transcription, making it a promising therapeutic target. In this study, we aimed to identify potent natural inhibitors that target conserved allosteric pockets within the RdRp polyribonucleotidyltransferase (PRNTase) domain of HMPV and HRSV using structure-based computational approaches.</p> Methods <p>We screened 100 Traditional Chinese Medicine (TCM)-derived phytochemicals through structure-based virtual screening against conserved RdRp allosteric sites. We then evaluated the top candidates based on their pharmacokinetic and toxicity profiles and conducted molecular dynamics (MD) simulations along with MM/GBSA free energy calculations to analyze the stability, conformational dynamics, and binding energetics of the protein–ligand complexes.</p> Results <p>We identified Tanshinone I, a diterpenoid from <i>Salvia miltiorrhiza</i> (Danshen), as the most potent inhibitor with binding energies of –9.1 kcal/mol (HMPV) and –9.5 kcal/mol (HRSV). It showed stronger binding affinities than FDA-approved antivirals Remdesivir (–8.5 and –8.0 kcal/mol) and Favipiravir (–5.9 and –6.2 kcal/mol), along with favorable pharmacokinetic properties, high bioavailability, and no predicted toxicity. MD simulations confirmed stable protein–ligand interactions with minimal fluctuations, and MM/GBSA analyses supported favorable binding energetics.</p> Conclusion <p>Our findings demonstrate that Tanshinone I acts as a promising dual inhibitor of HMPV and HRSV RdRp. Its high affinity, structural stability, and excellent drug-like properties support its potential as a lead compound for developing TCM-based antiviral therapies. Further in vitro and in vivo investigations are warranted to validate its therapeutic efficacy.</p> Graphical Abstract <p></p>

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In Silico Discovery of Tanshinone I, a Diterpenoid from Salvia miltiorrhiza (Danshen), as a Dual Antiviral Natural Inhibitor Targeting Conserved Allosteric Sites of HMPV and HRSV RNA-Dependent RNA Polymerases

  • 期刊论文

  • 发表日期：

    2025年11月10日

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  • Sayantika Debnath,
  • Uddalak Das,
  • Akshay Uttarkar,
  • Vidya Niranjan,
  • Arkajit De

摘要

Purpose

Human Metapneumovirus (HMPV) and Human Respiratory Syncytial Virus (HRSV) cause severe acute lower respiratory tract infections (ALRTIs), particularly in children, the elderly, and immunocompromised individuals. Despite their clinical significance, effective antiviral therapies remain limited. Both viruses rely on a conserved RNA-dependent RNA polymerase (RdRp) for replication and transcription, making it a promising therapeutic target. In this study, we aimed to identify potent natural inhibitors that target conserved allosteric pockets within the RdRp polyribonucleotidyltransferase (PRNTase) domain of HMPV and HRSV using structure-based computational approaches.

Methods

We screened 100 Traditional Chinese Medicine (TCM)-derived phytochemicals through structure-based virtual screening against conserved RdRp allosteric sites. We then evaluated the top candidates based on their pharmacokinetic and toxicity profiles and conducted molecular dynamics (MD) simulations along with MM/GBSA free energy calculations to analyze the stability, conformational dynamics, and binding energetics of the protein–ligand complexes.

Results

We identified Tanshinone I, a diterpenoid from Salvia miltiorrhiza (Danshen), as the most potent inhibitor with binding energies of –9.1 kcal/mol (HMPV) and –9.5 kcal/mol (HRSV). It showed stronger binding affinities than FDA-approved antivirals Remdesivir (–8.5 and –8.0 kcal/mol) and Favipiravir (–5.9 and –6.2 kcal/mol), along with favorable pharmacokinetic properties, high bioavailability, and no predicted toxicity. MD simulations confirmed stable protein–ligand interactions with minimal fluctuations, and MM/GBSA analyses supported favorable binding energetics.

Conclusion

Our findings demonstrate that Tanshinone I acts as a promising dual inhibitor of HMPV and HRSV RdRp. Its high affinity, structural stability, and excellent drug-like properties support its potential as a lead compound for developing TCM-based antiviral therapies. Further in vitro and in vivo investigations are warranted to validate its therapeutic efficacy.

Graphical Abstract