Molecular dynamics studies on the interactions of PTP1B with inhibitors: from the first phosphate-binding site to the second one.

Protein tyrosine phosphatases 1B (PTP1B) is a major negative regulator of both insulin and leptin signaling pathways. In view of this, it becomes an important target for drug development against cancers, diabetes and obesity. The aim of the current study is to use the long time-scale molecular dynamics (MD) simulations to investigate the structural and dynamic factors that cause its inhibition by INTA and INTB, the two most potent and highly selective PTP1B inhibitors known so far. In order to investigate the mode of collective motions that is vitally important to the biological function, the covariance matrix of C(alpha) atoms was introduced for performing the dynamic analysis of the inhibition systems. It has been observed that the conformational and dynamic features of WPD-Loop, R-Loop and S-Loop play a key role in providing a smooth entrance for the inhibitors moving into the binding pocket as well as a favorable microenvironment to stabilize them. Furthermore, the hydrogen bonding networks formed around the active site with INTA and INTB may be the main reason of why the inhibition of PTP1B by the two ligands is so potent and selective. All these findings might provide useful insights for developing novel and effective drugs to treat cancer, diabetes and obesity.