Ashutosh Singh

Celiac disease is an autoimmune enteropathy associated with the dietary protein, gluten, and affects specific populations carrying genes HLADQ2/8. Currently, the only available treatment is a lifelong gluten-free diet (GFD), and even when following a stringent GFD, about 30% of patients still have symptoms. Another important protein, Cathepsin S, specifically processes gluten proteins for presentation to these MHCs and is therefore a potential target for the disease. The study aims to use a drug repurposing or repositioning strategy to identify a potential Cathepsin S (CatS) inhibitor via a structure-based virtual screening method in drug discovery. The crystal structure of human CatS (PDB: 4P6G) was prepared using Schrödinger Suite and validated through PROCHECK analysis. Virtual screening was performed on 1,615 FDA-approved small molecules from the ZINC15 database using the Glide hierarchical workflow (HTVS, SP, and XP). Lead compounds were evaluated using MM-GBSA binding energy calculations, 100-ns molecular dynamics simulations with Desmond, and ADME property predictions with QikProp. With a docking score of − 9.396 kcal/mol and an MM-GBSA binding energy of − 53.09 kcal/mol, Pitavastatin (ZINC000001534965) was the top-ranked FDA-approved drug according to virtual screening. The second top-ranked compound was Lubiprostone (ZINC000004217732), with a docking score of − 8.935 kcal/mol and an MMGBSA binding energy of − 33.85 kcal/mol. Compared with the co-crystallised reference inhibitor 2FZ (− 7.920 kcal/mol), both compounds exhibited significantly improved binding affinity. Protein-ligand interactions were stable with RMSD values < 2.0 Å over 100 ns trajectories, according to molecular dynamics simulations (Pitavastatin: 1.31 ± 0.37 Å; Lubiprostone: 1.86 ± 0.32 Å). Both compounds exhibited excellent ADME profiles, characterised by favourable lipophilicity and adherence to Lipinski’s rule of five, with expected oral absorption exceeding 85% in humans. A focused screening of FDA-approved drugs identified pitavastatin and lubiprostone as promising cathepsin S inhibitors for CeD therapy. Established safety profiles and well-established pharmacokinetics are just a few of the substantial advantages these medicines offer for clinical translation.