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 (Ki 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.