Virtual structure-based docking, WaterMap, and molecular dynamics guided identification of the potential natural compounds as inhibitors of protein-tyrosine phosphatase 1B

Neuroinflammation is considered as the pathological hallmark of neurodegenerative diseases, including Alzheimer's disease (AD). Under inflammatory conditions, activation of microglial cells results in the increased expression of Protein tyrosine phosphatase 1B (PTP1B) levels, enhancing pro-inflammatory response. Computation based in silico docking studies were done using maestro interface to identify the inhibitors of PTP1B. A library of 1941 phytomolecules from Zinc database was screened for evaluation of their binding potential with PTP1B. Phytomolecules with better activity and binding were shortlisted after HTVS, SP, and XP mode of docking. The refining of the hit molecules was done by the analysis of the pharmacokinetic properties and toxicity prediction using QikProp tool. The molecules with better binding and pharmacokinetic properties were selected for WaterMap analysis and Molecular dynamics simulation study. The top three compounds were selected for further studies, including QikProp analysis, water map analysis, and molecular dynamics study. Compounds ZINC000001785780, ZINC000013543704, ZINC000040874044 were found to be potent inhibitors against PTP1B based on the docking score and binding interactions. Among the selected molecules, ZINC000013543704 showed better stability in the molecular dynamics simulation study and WaterMap study. The identified hit could be a potent inhibitor of PTP1B that further requires experimental validation using in vitro and in vivo experimental models.