Biochemical and Structural Studies of Protein Tyrosine Phosphatase PTP‐PEST (PTPN12) in Search of Small Molecule Inhibitors

ABSTRACT PTP‐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.