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
Abstract
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…
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