Old Drugs, New Targets: Molecular Docking Insights into Repurposing Proton Pump Inhibitors for the TLR4/MD-2, NLRP3, and C5aR1 Axes in Autoimmune Liver Diseases

Background/Objectives: Autoimmune liver diseases (AILDs), including autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis, may include treatment-resistant cases and therefore require new therapeutic strategies. This in silico study evaluated proton pump inhibitors (PPIs) across three pathophysiologically complementary inflammatory targets relevant to hepatic immune injury: TLR4/MD-2, representing upstream innate immune sensing; NLRP3, representing inflammasome-mediated inflammatory amplification; and C5aR1, representing complement-dependent leukocyte recruitment. Methods: The binding profiles of four PPIs (rabeprazole, lansoprazole, omeprazole, and pantoprazole) were analyzed by molecular docking against TLR4/MD-2 (3FXI), NLRP3 (7VTP and 7PZC), and C5aR1 (6C1R and 5O9H). TAK-242, MCC950, and avacopan were included as target-associated reference ligands solely to provide structural and protocol-specific context. Their docking scores were not used as benchmarks of relative binding affinity, inhibitory potency, or pharmacological efficacy. MM-GBSA binding free energy calculations for the best score in all proteins were performed. Molecular docking and molecular dynamics analyses indicated stable interactions for the best docking score. Results: PPIs showed variable but potentially meaningful docking affinities across the evaluated targets. Rabeprazole produced favorable docking scores within the investigated TLR4/MD-2 (−7.85 kcal/mol) and inactive NLRP3 (−9.10 kcal/mol) binding sites under the present docking protocol. The reference ligands TAK-242 and MCC950 were included only to provide structural and protocol-specific context, and their docking scores were not interpreted as measures of relative pharmacological potency. Among the PPIs, lansoprazole showed the most favorable docking score for the C5aR1 allosteric site (−6.93 kcal/mol). Interaction analyses suggested favorable hydrophobic contacts and substantial spatial occupancy within the investigated binding pockets; however, cross-target docking compatibility may partly reflect nonspecific hydrophobic accommodation rather than genuine polypharmacology, and whether these predicted interactions produce target-specific functional effects requires experimental validation. MM-GBSA analysis supported the predicted stability of the rabeprazole–NLRP3 (7PZC) complex (ΔGbind = −56.97 kcal/mol). Conclusions: These findings prioritize rabeprazole and lansoprazole as PPI scaffolds showing favorable predicted interactions across several inflammation-related target structures within the applied computational framework. These results are hypothesis-generating and do not establish target inhibition, target engagement, or therapeutic efficacy. The results are hypothesis-generating and warrant experimental studies to determine whether these predicted interactions translate into target engagement or modulation of inflammatory signaling in AILDs.