Virtual Screening of Novel and Selective Inhibitors of Protein Tyrosine Phosphatase 1B over T-Cell Protein Tyrosine Phosphatase Using a Bidentate Inhibition Strategy

Protein tyrosine phosphatase 1B (PTP1B), a promising target for type II diabetes, obesity, and cancer therapeutics, plays an important negative role in insulin signaling pathways. However, the lack of selectivity over other PTPs, especially for T-cell protein tyrosine phosphatase (TCPTP), is still a challenge for inhibitor development. Recent studies have suggested that the second phosphotyrosine (pTyr) binding site, close to the catalytic domain, may elevate binding affinity while bringing selectivity to inhibitors. Inspired by these studies, a virtual screening method based on a bidentate strategy was employed to identify novel selective inhibitors of PTP1B. Targeting both the active site and the second pTyr binding site of PTP1B, three compounds (CD00466, JFD02943, JFD02945) were found to be competitive inhibitors (K_i range from 1.79 to 10.49 μM). The most effective compound, CD00466, exhibited selectivity over TCPTP (31-fold). Using molecular dynamics simulation and the MM/GBSA binding free energy calculation, this study confirmed that the three inhibitors bound to PTP1B in a bidentate pattern. Our work indicates that bidentate virtual screening is a potential approach to the further investigation of selective PTP1B inhibitors.