Gladson David Masih

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.

Influenza A virus subtype H3N2 is a highly infectious respiratory virus that is responsible for global seasonal flu epidemics. The current study was designed to investigate the antiviral activity of 150 phytocompounds of North Western Himalayas medicinal plants by molecular docking. Two target proteins of hemagglutinin of influenza virus A (PDB ID 4WE8) and Influenza virus H3N2 nucleoprotein - R416A mutant (PDB ID 7NT8) are selected for this study. Molecular docking was done by AutoDock vina tool, toxicity and drug-likeness prediction was done by protox II and Moleinspiration. MD simulation of best protein-ligand complexes was done by using Gromacs, version 2021.5. Molecular docking and toxicity data revealed that clicoemodin and rumexocide showed the best binding with both target proteins 4WEB & 7NT8. Clicoemodin showed the -7.5 KJ/mol binding energy with 4WE8 and 7NT8. Similarly, rumexoside showed the -7.6 KJ/mol binding energy with 4WE8 and -7.6 KJ/mol with 7NT8. Furthermore, Molecular dynamic simulation and MMPBSA binding free energy validated the stability of protein-ligand complexes. The current study suggested that clicoemodin and rumexocide are the promising inhibitors of H3N2 proteins hemagglutinin of influenza virus A and Influenza virus H3N2 nucleoprotein - R416A mutant, though there is further in vitro and in vivo validation is required.Communicated by Ramaswamy H. Sarma.