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, as well as certain cancers. Although numerous inhibitors targeting the catalytic and allosteric sites have been reported, no drugs have been approved due to low-selectivity and a limited understanding of their inhibitory mechanisms. DPM-1001, an analog of specific PTP1B inhibitor (trodusquemine), is a potent, specific, and non-competitive inhibitor of PTP1B. However, its co-crystal structure bound to PTP1B has been unresolved. To perform enzymatic function of PTP1B, the “WPD loop” at catalytic site must transit between open (inactive) and closed (active) states. To understand the effect of ligand binding at the allosteric site on the state of the WPD loop, we constructed PTB1B model systems with and without DPM-1001 at allosteric site and performed molecular dynamics (MD) simulations of them. Our MD simulations revealed that DPM-1001 disrupted interactions within PTP1B and holed on the catalytic loop to open (inactive) state. This elucidation of the allosteric mechanism will provide crucial insights for the rational design of more potent, selective, and therapeutically potent PTP1B inhibitors.
Yano et al. (Sun,) studied this question.