Structure-based discovery of small molecule inhibitors targeted to protein tyrosine phosphatase 1B

Mauro Sarmiento, Li Wu, Yen Fang Keng, Li Song, Zhaowen Luo, Ziwei Huang, Guo Zhang Wu, Adam K. Yuan, Zhong-Yin Zhang

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Protein tyrosine phosphatases (PTPases) are involved in the control of tyrosine phosphorylation levels in the cell and are believed to be crucial for the regulation of a multitude of cellular functions. A detailed understanding of the role played by PTPases in various signaling pathways has not yet been achieved, and potent and selective PTPase inhibitors are essential in the quest to determine the functionality of individual PTPases. Using the DOCK methodology, we have carried out a structure-based, computer- assisted search of an available chemical database in order to identify low molecular weight, nonpeptidic PTP1B inhibitors. We have identified several organic molecules that not only possess inhibitory activity against PTP1B but which also display significant selectivity for PTP1B. This indicates that although structural features important for pTyr recognition are conserved among different PTPases, it is possible to generate selective inhibitors targeted primarily to the catalytic site. Kinetic analysis and molecular modeling experiments suggest that the PTP1B active site possesses significant plasticity such that substituted and extended aromatic systems can be accommodated. The newly identified molecules provide a molecular framework upon which therapeutically useful compounds can ultimately be based, and systematic optimization of these lead compounds is likely to further enhance their potency and selectivity.

Original languageEnglish (US)
Pages (from-to)146-155
Number of pages10
JournalJournal of Medicinal Chemistry
Volume43
Issue number2
DOIs
StatePublished - Jan 27 2000
Externally publishedYes

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Protein Tyrosine Phosphatases
Molecules
Catalytic Domain
Chemical Databases
Lead compounds
Phosphorylation
Molecular modeling
Plasticity
Tyrosine
Molecular Weight
Molecular weight
Kinetics
Experiments

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Structure-based discovery of small molecule inhibitors targeted to protein tyrosine phosphatase 1B. / Sarmiento, Mauro; Wu, Li; Keng, Yen Fang; Song, Li; Luo, Zhaowen; Huang, Ziwei; Wu, Guo Zhang; Yuan, Adam K.; Zhang, Zhong-Yin.

In: Journal of Medicinal Chemistry, Vol. 43, No. 2, 27.01.2000, p. 146-155.

Research output: Contribution to journalArticle

Sarmiento, M, Wu, L, Keng, YF, Song, L, Luo, Z, Huang, Z, Wu, GZ, Yuan, AK & Zhang, Z-Y 2000, 'Structure-based discovery of small molecule inhibitors targeted to protein tyrosine phosphatase 1B', Journal of Medicinal Chemistry, vol. 43, no. 2, pp. 146-155. https://doi.org/10.1021/jm990329z
Sarmiento, Mauro ; Wu, Li ; Keng, Yen Fang ; Song, Li ; Luo, Zhaowen ; Huang, Ziwei ; Wu, Guo Zhang ; Yuan, Adam K. ; Zhang, Zhong-Yin. / Structure-based discovery of small molecule inhibitors targeted to protein tyrosine phosphatase 1B. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 2. pp. 146-155.
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