In Silico Screening for PTPN22 Inhibitors: Active Hits from an Inactive Phosphatase Conformation

2‐Benzamidobenzoic acids seem to stabilize PTPN22 phosphatase in its inactive 'open' conformation with the WPD loop locked in a distal position. In silico screening using both 3D structures in open and closed conformations yielded potent inhibitors of this potential drug target for autoimmunity that specifically dock into its open form. Tryptophan fluorescence measurements support the proposed binding mode.

[1]  Thomas Lengauer,et al.  A fast flexible docking method using an incremental construction algorithm. , 1996, Journal of molecular biology.

[2]  T. Mustelin,et al.  Targeting the PTPome in human disease , 2006, Expert opinion on therapeutic targets.

[3]  E. Shaoul,et al.  Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. , 1999, Blood.

[4]  T. Mustelin,et al.  Strategies for developing protein tyrosine phosphatase inhibitors. , 2007, Methods.

[5]  Torsten Schwede,et al.  The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling , 2006, Bioinform..

[6]  R Abagyan,et al.  Flexible protein–ligand docking by global energy optimization in internal coordinates , 1997, Proteins.

[7]  Nunzio Bottini,et al.  Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant , 2005, Nature Genetics.

[8]  Zhon-Yin Zhang,et al.  Protein tyrosine phosphatases: structure and function, substrate specificity, and inhibitor development. , 2002, Annual review of pharmacology and toxicology.

[9]  Andy Hudmon,et al.  Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseases , 2007, Proceedings of the National Academy of Sciences.

[10]  H. Waldmann,et al.  Inhibitoren der Proteintyrosinphosphatasen: Kandidaten für zukünftige Wirkstoffe? , 2005 .

[11]  T. Hunter,et al.  Transforming gene product of Rous sarcoma virus phosphorylates tyrosine , 1980, Proceedings of the National Academy of Sciences.

[12]  Nunzio Bottini,et al.  A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes , 2004, Nature Genetics.

[13]  Kristin G Ardlie,et al.  Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. , 2004, American journal of human genetics.

[14]  N. Bottini,et al.  Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes. , 2005, Human immunology.

[15]  Annette Lee,et al.  A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. , 2004, American journal of human genetics.

[16]  H. Waldmann,et al.  Inhibitors of protein tyrosine phosphatases: next-generation drugs? , 2005, Angewandte Chemie.

[17]  Brian Hudson,et al.  Strategic Pooling of Compounds for High-Throughput Screening , 1999, J. Chem. Inf. Comput. Sci..

[18]  Joanna M. Sasin,et al.  Protein Tyrosine Phosphatases in the Human Genome , 2004, Cell.

[19]  T. Mustelin,et al.  Protein tyrosine phosphatases in autoimmunity. , 2008, Annual review of immunology.