Computational study of natural and FDA-approved compounds binding to wild-type and P۱۳۵Q mutant HBcAg

Hepatitis B virus (HBV) infection remains a global health challenge, and mutations in the core antigen (HBcAg) can compromise the efficacy of current antiviral therapies. This study aimed to identify potential natural and FDA-approved compounds targeting wild-type (WPr) and P۱۳۵Q mutant (MPr) HBcAg using a comprehensive in silico approach. Natural compounds were filtered using Lipinski's Rule of Five and ADMET profiling. Molecular docking was performed using AutoDock Vina (version ۱.۲.x, ۲۰۲۱), and the top-ranked complexes were subjected to ۵۰۰ ns molecular dynamics simulations using GROMACS ۲۰۲۳ with the AMBER۹۹SB force field. Structural and energetic analyses included RMSD, RMSF, radius of gyration (Rg), solvent-accessible surface area (SASA), hydrogen bonding, principal component analysis (PCA), and MM/PBSA binding free energy calculations. Among ۵,۰۰۰  screened phytochemicals, Carnosic acid (Csa) and Nordentatin (Nor) demonstrated favorable binding affinities (ΔG = −۸.۸۵ and −۹.۸۴ kcal/mol, respectively) with acceptable ADMET profiles. MD simulations revealed distinct binding mechanisms: Csa stabilized WPr through electrostatic interactions, while Nor stabilized MPr through persistent hydrogen bonds and van der Waals contacts involving Trp۱۰۲, Ser۱۰۶, and Tyr۱۱۸. Binding free energy analysis suggested that Csa may have stronger affinity for the mutant form, whereas Nor appeared to favor the wild-type. The P۱۳۵Q mutation significantly influenced ligand binding dynamics and interaction patterns, highlighting the structural differences between wild-type and mutant HBcAg. Our computational findings suggest that Csa and Nor may serve as potential candidates for HBcAg binding. However, these predictions are purely computational and require experimental validation to confirm their actual biological activity.

کلیدواژه ها:

Anti-HBV ، Carnosic acid ، HBcAg ، Molecular Dynamics ، Nordentatin ، P۱۳۵Q mutation