Screening of Propolis compounds reveals potential inhibitors of rhinovirus 3C protease: A computational study

Rhinoviruses are major causes of respiratory infections and often aggravate conditions such as asthma. The protein 3C protease plays a crucial role as it blocks the virus replication. This study explores the potential of natural inhibitors, specifically Propolis compounds targeting the protein 3Cpro, which is a promising and less toxic alternative compared to the standard synthetic inhibitor, Rupintrivir.

A set of 60 propolis-derived molecules was selected and prepared for molecular docking simulations to evaluate their binding affinity to 3Cpro, then ligand-3Cpro protein interactions were visualized. A 200ns molecular dynamics (MD) simulation was conducted to assess the stability of the protein-ligand complexes, then the following MD parameters were analyzed: RMSD, RMSF, SASA, Rg, and hydrogen bonding. Binding free energies were further estimated using MM-PBSA, and per-residue energy decomposition was performed to identify key stabilizing interactions.

The potential compounds Rutin and Retusapurpurin A displayed binding energies of -8.0 kcal/mol and -8.78 kcal/mol, respectively, outperforming the reference inhibitor Rupintrivir (-6.66 kcal/mol). MD simulations revealed that both ligands effectively stabilize 3Cpro, with RMSD scores of 1.02 ± 0.10 nm and 1,21 ± 0.22, respectively, and are also more stable in the pocket than Rupintrivir. These ligands also reduced RMSF, SASA, and Rg scores. MM-PBSA calculations showed more favorable binding energies for Rutin (-35.65 kcal/mol) and Retusapurpurin A (-31.59 kcal/mol) compared to Rupintrivir (-25.44 kcal/mol). Per-residue decomposition further revealed strong energetic contributions from catalytic site residues (His40, Glu71, and Cys147), especially in the Rutin complex.

The potential compounds Rutin and Retusapurpurin A are promising inhibitors targeting 3Cpro, exhibiting elevated potential efficacy compared to Rupintrivir. These results pave the way for the development of natural antivirals derived from Propolis and support its use as a dietary supplement for the treatment of rhinovirus infections. The chemical diversity of Propolis could limit the emergence of viral resistance. However, in vitro and in vivo experimental validation is required to confirm these observations.