Johnson, DelnaDelnaJohnsonDixit, MadhulikaMadhulikaDixitKirubakaran, SivapriyaSivapriyaKirubakaran2025-08-312025-08-312025-02-0110.1111/cbdd.700582-s2.0-85216748141https://d8.irins.org/handle/IITG2025/2827039895370PTP-PEST (also known as PTPN12) regulates cellular signaling and transduction pathways by dephosphorylating its substrate. PTP-PEST is considered an important drug target owing to its involvement in cancer progression and myocardial injury. Till now only a few inhibitors are currently being studied in the inhibition of PTP-PEST, majorly belonging to the class of metal-based drugs. In this study, we aimed to investigate small molecules that could potentially inhibit PTP-PEST for further development of PTP-PEST inhibitors. As an approach, we used an in silico molecular docking technique to screen an in-house synthesized molecular library. Further, we validated the docking results by in vitro inhibition screening of the best molecules using the purified catalytic domain of human PTP-PEST, which was over-expressed in E.coli. We identified a myo-inositol based derivative, J1-65, which binds to PTP-PEST and results in the competitive inhibition of the protein. Further, we confirmed this protein-ligand binding using binding affinity studies based on protein thermal shift assay and in silico molecular dynamic simulations. Our efforts to discover a novel scaffold for inhibiting hPTP-PEST mark a crucial stride in laying the groundwork for the future development of selective PTP-PEST inhibitors.falsecompetitive inhibition | in silico | in vitro | molecular dynamic simulations | phosphataseArticle17470285February 20250e70058arJournal0WOS:001411092900001