Structure-Based Identification of Natural Inhibitors Targeting the Gc Glycoprotein of Oropouche Virus: An In Silico...

Area of Science:

• Virology
• Drug Discovery
• Computational Chemistry

Background:

• Oropouche virus (OROV) is an emerging orthobunyavirus in the Americas with significant public health implications.
• There are currently no approved antiviral therapies for OROV infections.
• The Gc glycoprotein is crucial for OROV host cell entry, making it a key target for antiviral development.

Purpose of the Study:

• To identify natural antiviral compounds targeting the OROV Gc glycoprotein using a structure-based in silico approach.
• To screen a library of plant-derived compounds for their potential to inhibit OROV fusion.
• To evaluate the binding stability and mechanism of action of potential drug candidates.

Main Methods:

• Screened 537 plant-derived compounds against the OROV Gc head domain using molecular docking.
• Performed molecular dynamics simulations and MM-PBSA free energy calculations to assess binding affinity and stability.
• Conducted ADMET profiling to predict pharmacokinetic properties and potential toxicity.
• Analyzed residue-level fluctuations (RMSF) to understand the impact on Gc protein dynamics.

Main Results:

• Curcumin and berberine were identified as lead candidates with favorable binding characteristics.
• Curcumin showed stable binding (-38.14 kcal/mol) and conformational stability (RMSD 1.82 Å, Rg ~ 18.8 Å).
• Berberine exhibited strong binding energy (-13.10 kcal/mol) and dynamic stability (RMSD 1.86 Å, Rg ~ 19.0 Å), despite predicted cytotoxicity.
• Both compounds reduced fluctuations in critical Gc regions, suggesting interference with viral fusion.

Conclusions:

• Curcumin and berberine are promising natural scaffolds for developing novel anti-OROV antiviral drugs.
• These compounds may act by stabilizing the Gc prefusion conformation, hindering viral entry.
• The study provides a rational basis for experimental validation of these compounds against OROV.