Identification of PTP1B Allosteric Inhibitors Through Virtual Screening

Protein tyrosine phosphatase 1B (PTP1B), a prototypical member of the PTP family, has been identified as a key therapeutic target for Type 2 Diabetes Mellitus (T2DM). More recently, PTP1B has emerged as a regulator of immune responses in cancer, further highlighting its potential for metabolic and immunomodulatory therapies. However, the high conservation of the catalytic site across the PTP family has made the development of selective PTP1B inhibitors challenging. To overcome this limitation, recent efforts have focused on allosteric inhibition, particularly through benzofuran sulfonamide derivatives, which offer a promising route to achieve selectivity. Here, we report the virtual screening approach toward the identification of several potent and selective allosteric inhibitors of PTP1B. Using the co-crystal structure of PTP1B bound with a known allosteric ligand, we screened a library of 32,596 compounds against the allosteric pocket and identified 81 candidate compounds with high affinity. 3 representative compounds were chosen manually by structural uniqueness for further studies, including Prime MM-GBSA analysis and Molecular Dynamics (MD) simulation experiment. ADME analyses and Density Functional Theory (DFT) calculations were assessed to further characterize the pharmacokinetic behavior and interaction potential of the screened compounds. Together, these findings establish a structural and dynamic framework for designing selective PTP1B allosteric inhibitors, offering new opportunities for therapeutic development in diabetes and cancer immunotherapy.