Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B

Several protein-tyrosine phosphatases (PTPs) have been proposed to act as n egative regulators of insulin signaling. Recent studies have shown increase d insulin sensitivity and resistance to obesity in PTP1B knockout mice, thu s pointing to this enzyme as a potential drug target in diabetes. Structure -based design, guided by PTP mutants and x-ray protein crystallography, was used to optimize a relatively weak, nonphosphorus, nonpeptide general PTP inhibitor (2-(oxalyl-amino)-benzoic acid) into a highly selective PTP1B inh ibitor. This was achieved by addressing residue 48 as a selectivity determi ning residue. Ey introducing a basic nitrogen in the core structure of the inhibitor, a salt bridge was formed to Asp-48 in PTP1B, In contrast, the ba sic nitrogen causes repulsion in other PTPs containing an asparagine in the equivalent position resulting in a remarkable selectivity for PTP1B, Impor tantly, this was accomplished while retaining the molecular weight of the i nhibitor below 300 g/mol.