Allosteric inhibition mechanism of PTP1B by DPM-1001 using molecular dynamics simulation

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin and leptin signaling and has emerged as a promising therapeutic target for metabolic disorders such as diabetes and obesity. DPM-1001 is a potential PTP1B inhibitor with specificity that is noncompetitive. However, its co-crystal structure bound to PTP1B has been unresolved, and the inhibition mechanism has not been understood. PTP1B functions with the open (inactive)/closed (active) conformation transition of the WPD loop at the catalytic site. In this study, to understand the effect of ligand binding at the allosteric site on the conformational stability of the WPD loop, we constructed PTB1B model systems with and without DPM-1001 bound at the allosteric site, and we performed molecular dynamics simulations for these systems. Our results indicate that DPM-1001 disrupts the triangle interactions among loop 11, α3 helix and α7 helix of PTP1B. Furthermore, DPM-1001 locks Leu192, a key residue of the α3 helix exposed to the WPD loop, thereby stabilizing the catalytic loop in the open conformation. This elucidation of the allosteric mechanism will contribute to the rational design of more potent and selective PTP1B inhibitors.