Identification of natural products as selective PTP1B inhibitors via virtual screening.

A hierarchical virtual screening was applied to identify natural products as new prototypes of PTP1B inhibitors. Ten compounds exhibited IC 50 values at the micromolar level, and nine of them demonstrated evident selectivity to PTP1B over four other PTPs. • Natural hits were identified as PTP1B inhibitors by virtual screening. • Ten hits demonstrated excellent potency with IC 50 at micromolar level against PTP1B. • Several hits showed evident selectivity to PTP1B over four other PTPs, including TCPTP. • A linear furancoumarin skeleton was recognized as a new prototype for PTP1B inhibitors. Protein tyrosine phosphatase 1B (PTP1B) is emerging as a promising yet challenging target for drug discovery. To identify natural products as new prototypes for PTP1B inhibitors, we employed a hierarchical protocol combining ligand-based and structure-based approaches for virtual screening against natural product libraries. Twenty-six compounds were prioritized for enzymatic evaluation against PTP1B, and ten of them were recognized as potent PTP1B inhibitors with IC 50 values at the micromolar level. Notably, nine compounds demonstrated evident selectivity to PTP1B over four other PTPs, including the most homologous T -cell protein tyrosine phosphatase (TCPTP). The results implicated that the structural uniqueness of the natural products might be a potential solution to the selectivity issue associated with the target PTP1B. [ABSTRACT FROM AUTHOR]