Network pharmacology analysis of drugs targeting feline infectious peritonitis virus main protease in Felis catus

Feline infectious peritonitis (FIP) is a fatal systemic disease of cats. FIP is caused by feline infectious peritonitis virus (FIPV), for which effective, approved antiviral therapies are limited. The viral main protease (Mpro) is essential for viral replication, making it an attractive therapeutic target. This study aimed to identify high-affinity inhibitors of FIPV Mpro and to evaluate their potential safety and pharmacological profiles using an integrated network pharmacology approach in Felis catus. The crystal structure of FIPV Mpro (PDB ID: 5EU8) was used for molecular docking with eleven antiviral compounds using AutoDock Vina. Compounds with the highest affinity (IC50 < 25 µM) to FIPV Mpro were subjected to target prediction, mapping of human targets to feline orthologs, construction of protein-protein interaction networks, Markov Cluster Algorithm (MCL) clustering, and functional enrichment analyses. All tested compounds demonstrated pharmacologically feasible binding to FIPV Mpro (IC50: 5 to 187 µM). Network pharmacology analysis showed that high-affinity compounds differentially modulated host pathways related to cell cycle regulation, kinase signalling, extracellular matrix remodelling, metabolism, and immune-associated pathways. GS441524 derivatives showed a balanced host-interaction profile consistent with a favourable safety pharmacology profile, while Remdesivir and Balapiravir displayed broader signalling-pathway targeting, suggesting a need for cautious safety evaluation. The findings support the preference of GS441524 derivatives for FIP therapy and establish a robust computational framework for evaluating the efficacy and safety of potential antiviral candidates against FIPV.