Abstract
Over expressing in PTPN1 (encoding Protein tyrosine phosphatase 1B, PTP1B), a protein tyrosine phosphatase (PTP) that plays an overall positive role in insulin signaling, is linked to the pathogenesis of diabetes and obesity. The relationship between PTP1B and human diseases exhibits PTP1B as the target to treat these diseases. In this article, small weight molecules of the imidazolidine series were screened from databases and optimized on silicon as the inhibitors of PTP1B based on the steric conformation and electronic configuration of thiazolidinedione (TZD) compounds. The top three candidates were tested using an in vitro biological assay after synthesis. Finally, we report a novel inhibitor, Compound 13, that specifically inhibits PTP1B over the closely related phosphatase Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) at 80 μM. Its IC50 values are reported in this paper as well. This compound was further verified by computer analysis for its ability to combine the catalytic domains of PTP1B and SHP-2 by molecular dynamics (MD) simulations.
Highlights
Reversible protein tyrosine phosphorylation catalyzed by the coordinated actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) is of paramount importance in the regulation of the signaling events that underlie such fundamental processes as growth and proliferation, differentiation and survival or apoptosis, as well as adhesion and motility [1]
In order to obtain specific inhibitors of PTP1B over SHP-2, the FA part was replaced by other segments of the fragment database to extend its length to site B
Each structure of the 20 candidates was redocked into the two receptors, PTP1B and SHP-2, respectively
Summary
Reversible protein tyrosine phosphorylation catalyzed by the coordinated actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) is of paramount importance in the regulation of the signaling events that underlie such fundamental processes as growth and proliferation, differentiation and survival or apoptosis, as well as adhesion and motility [1]. PTPs constitute a large, structurally diverse family of receptor-like and cytoplasmic enzymes expressed in all eukaryotes. Indicated that large numbers of PTP genes were encoded within the human genome, including trans-membrane, receptor-like, and intracellular, non receptor-like enzymes. PTPs have positive (signal-enhancing) or negative (signal-attenuating) roles in a variety of normal signal transductions [3]. PTPs have been shown to be negative regulators of the insulin receptor. Inhibition of PTPs may be an effective method in the treatment of type 2 diabetes [4]
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