MUTATION-INDUCED ALTERATIONS IN LIGAND BINDING OF CARBOXYPEPTIDASE A1: A COMPARATIVE MOLECULAR DOCKING STUDY IN PANCREATITIS

Pancreatitis is a complex inflammatory disorder in which genetic variations in digestive enzymes can influence protein stability and interaction behavior.[1–4] Carboxypeptidase A1 (CPA1), a zinc-dependent metalloprotease involved in protein digestion, has been associated with mutation-driven structural alterations in pancreatic disease.[5–8] The present study aimed to evaluate the structural impact of a Ser34→Ala substitution in CPA1 through comparative molecular docking analysis. The wild-type and mutant protein structures were prepared and docked with phenylalanine, paracetamol, and ibuprofen using Auto Dock Vina.[12] Binding affinities and zinc–ligand distances were analyzed to assess mutation-induced changes in interaction patterns. Docking results revealed modest, ligand-dependent variations in binding affinity between the two protein forms. Phenylalanine exhibited slightly stronger predicted binding to the mutant structure, whereas paracetamol showed nearly identical affinities in both forms. Ibuprofen demonstrated the highest overall binding affinity but displayed a marginally stronger interaction with the wild-type protein. In all cases, Zn–O distances in the best-ranked docking poses exceeded 5 Å, indicating the absence of direct zinc coordination and suggesting peripheral binding within the catalytic cavity.[5,21] These findings suggest that the Ser34→Ala substitution induces subtle modifications in the ligand-binding environment without significantly disrupting the zinc-centered catalytic architecture of CPA1.[5,7] The study highlights the importance of mutation-aware structural evaluation in understanding enzyme–ligand interactions and provides a computational foundation for further experimental investigation in pancreatitis-related protein variants.