Natural Product-Based Virtual Screening Identifies Potential Inhibitors of Feline Coronavirus 3CLpro

Area of Science:

• Veterinary Virology
• Computational Chemistry
• Drug Discovery

Background:

• Feline infectious peritonitis (FIP) is a fatal disease caused by feline coronavirus (FCoV).
• Natural product virtual screening is a promising strategy for identifying FCoV antiviral agents.
• Targeting the FCoV 3C-like protease (3CLpro) is a key strategy for antiviral development.

Purpose of the Study:

• To discover potential inhibitors of the FCoV 3CLpro using a structure-based computational approach.
• To identify natural compounds with high binding affinity and stability against FCoV 3CLpro.
• To provide a foundation for structure-guided drug design against FCoV.

Main Methods:

• Screening of 96,677 natural compounds from the ZINC database using molecular docking.
• Refinement of initial hits based on ADMET properties and binding pose analysis.
• Molecular dynamics simulations and binding free energy calculations for further assessment.

Main Results:

• 14 compounds demonstrated stable interactions and minimal conformational changes with FCoV 3CLpro.
• Key residues (His162, Glu165, Cys144) were identified as crucial for stabilizing protein-ligand complexes.
• Eight compounds maintained stable binding profiles over 500-nanosecond simulations with high binding free energy.

Conclusions:

• The identified compounds show significant potential as antiviral leads for FCoV infections.
• Specific molecular frameworks were revealed, offering a basis for designing novel FCoV 3CLpro inhibitors.
• The study lays the groundwork for structure-guided drug discovery efforts targeting FCoV.