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Context <p>Human metapneumovirus (HMPV) is a significant cause of acute lower respiratory tract infections, particularly among pediatric, elderly, and immunocompromised populations, with no approved targeted antiviral therapy currently available. The prefusion conformation of the viral fusion (F) glycoprotein (PDB ID: 5WB0) is essential for membrane fusion and viral entry, representing a promising therapeutic target. In this study, a structurally diverse library of natural compounds was systematically screened to identify potential inhibitors of the HMPV F protein.</p> Methods <p>An integrated computational framework combining virtual screening, molecular docking, long-timescale molecular dynamics (MD) simulations, and density functional theory (DFT) calculations was employed. Virtual screening and docking were performed using AutoDock Vina, followed by rigorous binding pose validation. The top-ranked compounds—epigallocatechin gallate (EGCG), rutin, and quercetin—were subjected to 1000&#xa0;ns MD simulations (in triplicate) using GROMACS 2022 with explicit solvent conditions (TIP3P water model, physiological ionic strength). Binding free energies were estimated via MM-GBSA, and residue-level dynamics were analyzed using RMSD, RMSF, and dynamic cross-correlation matrices. Electronic properties were evaluated at the B3LYP/6-31G(d,p) level using Gaussian 16, including HOMO–LUMO gap analysis and molecular electrostatic potential (MEP) mapping. Pharmacokinetic and toxicity profiles were predicted using SwissADME, pkCSM, and ProTox-II.</p> Results <p>Docking analysis revealed that EGCG, rutin, and quercetin exhibit stronger binding affinities than the reference antiviral ribavirin, driven by extensive hydrogen bonding, π–π stacking, and van der Waals interactions within the functional binding pocket of the F protein. MD simulations demonstrated enhanced structural stability of these complexes, with EGCG showing the lowest conformational deviation and most favorable binding free energy. Correlated residue motion analysis further indicated ligand-induced stabilization of key functional regions. DFT-derived electronic descriptors, including reduced HOMO–LUMO gaps and favorable electrostatic distributions, supported the high reactivity and binding propensity of the selected compounds. ADMET predictions suggested acceptable pharmacokinetic profiles with low predicted toxicity.</p> Conclusion <p>This study identifies EGCG, rutin, and quercetin as promising natural inhibitors of the HMPV fusion protein, providing mechanistic insights into their binding behavior and stability. These findings offer a strong computational foundation for further experimental validation and rational antiviral drug development targeting HMPV.</p>

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Suppressing viral assembly in human metapneumovirus by targeting fusion protein with natural compounds: a structural dynamics and energetics study

  • 期刊论文

  • 发表日期：

    2026年4月27日

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  • Amit Dubey,
  • Manish Kumar,
  • Aisha Tufail

摘要

Context

Human metapneumovirus (HMPV) is a significant cause of acute lower respiratory tract infections, particularly among pediatric, elderly, and immunocompromised populations, with no approved targeted antiviral therapy currently available. The prefusion conformation of the viral fusion (F) glycoprotein (PDB ID: 5WB0) is essential for membrane fusion and viral entry, representing a promising therapeutic target. In this study, a structurally diverse library of natural compounds was systematically screened to identify potential inhibitors of the HMPV F protein.

Methods

An integrated computational framework combining virtual screening, molecular docking, long-timescale molecular dynamics (MD) simulations, and density functional theory (DFT) calculations was employed. Virtual screening and docking were performed using AutoDock Vina, followed by rigorous binding pose validation. The top-ranked compounds—epigallocatechin gallate (EGCG), rutin, and quercetin—were subjected to 1000 ns MD simulations (in triplicate) using GROMACS 2022 with explicit solvent conditions (TIP3P water model, physiological ionic strength). Binding free energies were estimated via MM-GBSA, and residue-level dynamics were analyzed using RMSD, RMSF, and dynamic cross-correlation matrices. Electronic properties were evaluated at the B3LYP/6-31G(d,p) level using Gaussian 16, including HOMO–LUMO gap analysis and molecular electrostatic potential (MEP) mapping. Pharmacokinetic and toxicity profiles were predicted using SwissADME, pkCSM, and ProTox-II.

Results

Docking analysis revealed that EGCG, rutin, and quercetin exhibit stronger binding affinities than the reference antiviral ribavirin, driven by extensive hydrogen bonding, π–π stacking, and van der Waals interactions within the functional binding pocket of the F protein. MD simulations demonstrated enhanced structural stability of these complexes, with EGCG showing the lowest conformational deviation and most favorable binding free energy. Correlated residue motion analysis further indicated ligand-induced stabilization of key functional regions. DFT-derived electronic descriptors, including reduced HOMO–LUMO gaps and favorable electrostatic distributions, supported the high reactivity and binding propensity of the selected compounds. ADMET predictions suggested acceptable pharmacokinetic profiles with low predicted toxicity.

Conclusion

This study identifies EGCG, rutin, and quercetin as promising natural inhibitors of the HMPV fusion protein, providing mechanistic insights into their binding behavior and stability. These findings offer a strong computational foundation for further experimental validation and rational antiviral drug development targeting HMPV.