Design, Synthesis, Biological Activity and Molecular Dynamics Studies of Specific Protein Tyrosine Phosphatase 1B Inhibitors over SHP-2

International Journal of Molecular Sciences

Su-Xia Sun¹  Xiao-Bo Li¹  Wen-Bo Liu¹  Ying Ma¹  Run-Ling Wang¹  Xian-Chao Cheng¹  Shu-Qing Wang¹ 

[1] Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, No.22 of Qixiangtai Road, Heping, Tianjin 300070, China; E-Mails:

关键词: PTP1B;    SHP-2;    synthesis;    imidazolidine;    activity;    molecular dynamics;   

DOI  :  10.3390/ijms140612661

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland