Identifying potential inhibitors of C-X-C motif chemokine ligand10 against vitiligo: structure-based virtual screening, molecular dynamics simulation, and principal component analysis

The research aims to envisage small molecule inhibitors targeting the C-X-C motif chemokine ligand 10 (CXCL10) of the JAK/STAT pathway. CXCL10 plays a significant role in inducing auto-immunity in vitiligo through JAK/STAT pathway. To accomplish the aim, structure-based virtual screening with fundamental search limits, e.g., molecular weight (MW & LE; 500 Da), hydrogen bond donor (HBD & LE; 5), hydrogen bond acceptor (HBA & LE; 10), and lipophilicity (logP & LE; 5) was used to screen investigational molecules from MCULE database. The SBVS-ligand hits were sifted through toxicity profiling followed by filtration through the Brain or IntestinaL EstimateD-Egg model to check the human intestinal abortion and blood-brain barrier permeation based on two physicochemical properties, including topological surface area and WLOGP. The BOILED-Egg filtered compounds were passed through drug-likeness features other than Pfizer's Lipinski rule of five, viz., Ghose filters, Muegge filters, Egan parameters, and Veber filters, followed by medicinal chemistry's pan assay interference structure and Brenk alert investigation. Chemical compounds that comply with the above ADME descriptors were docked with target protein CXCL10 via AutoDock Vina. The stability of the top two ligand hits was assessed through dynamics simulations of 100 ns and principal component analysis and compared with the reference drugs Baicalein and EGCG. Based on the findings of Gibbs free energy of binding, ADME profiling, medicinal chemistry attributes depiction, root-mean-square deviation, root-mean-square fluctuation, solvent accessible surface area, the free energy of solvation, the radius of gyration, and PCA, MCULE2726078782-0-2 was found better than potential reference drug Baicalein.Communicated by Ramaswamy H. Sarma

Automated summary

The research aims to design small molecule inhibitors that can target CXCL10 in the JAK/STAT pathway. Structure-based virtual screening was used to identify potential compounds from the MCULE database, followed by toxicity profiling and ADME evaluation. The top two ligands were further assessed through molecular dynamics simulations and compared with reference drugs. MCULE2726078782-0-2 showed better performance than Baicalein based on various parameters.