Identification of natural products as selective PTP1B inhibitors via virtual screening

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 IC₅₀ 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.