Identifying Natural Products as Feline Coronavirus M^pro Inhibitors by Structural-Based Virtual Screening and...

Area of Science:

• Veterinary Virology
• Drug Discovery
• Computational Chemistry

Background:

• Feline coronavirus (FCoV) causes feline infectious peritonitis (FIP), a fatal disease in cats.
• The viral main protease (Mpro) is essential for FCoV replication and a critical drug target.

Purpose of the Study:

• To identify potent and low-toxicity natural compounds that inhibit FCoV Mpro.
• To explore the binding interactions of these compounds with the Mpro active site.

Main Methods:

• Virtual screening of a natural product library against FCoV Mpro.
• Enzyme inhibition assays to determine the efficacy of selected compounds.
• Molecular dynamics simulations and binding free energy calculations to analyze interactions.

Main Results:

• Eighty-six compounds were initially selected based on docking scores.
• Twelve compounds demonstrated over 40% inhibition of Mpro at 200 μmol/L.
• Theaflavin 3,3'-digallate, sennoside C, pinocembrin-galloyl-HHDP-G, and thonningianin A showed IC50 values ranging from 25.0 to 50.6 μmol/L.
• Curcuminoids and flavonoids also exhibited notable inhibitory activity.
• Simulations revealed key interactions between compounds and Mpro active site residues (His-41, Cys-144, Glu-165).

Conclusions:

• Natural products, particularly theaflavin 3,3'-digallate and sennoside C, are effective inhibitors of FCoV Mpro.
• These identified compounds represent promising leads for developing novel FIP therapeutics.
• Detailed binding analyses provide insights for future drug design and optimization.