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