2cnf: Difference between revisions

Structural analyses of the protein-tyrosine phosphatase 1B (PTP1B) active, site and inhibitor complexes have aided in optimization of a peptide, inhibitor containing the novel (S)-isothiazolidinone (IZD) phosphonate, mimetic. Potency and permeability were simultaneously improved by, replacing the polar peptidic backbone of the inhibitor with nonpeptidic, moieties. The C-terminal primary amide was replaced with a benzimidazole, ring, which hydrogen bonds to the carboxylate of Asp(48), and the N, terminus of the peptide was replaced with an aryl sulfonamide, which, hydrogen bonds to Asp(48) and the backbone NH of Arg(47) via a water, molecule. Although both substituents retain the favorable hydrogen bonding, network of the peptide scaffold, their aryl rings interact weakly with the, protein. The aryl ring of benzimidazole is partially solvent exposed and, only participates in van der Waals interactions with Phe(182) of the flap., The aryl ring of aryl sulfonamide adopts an unexpected conformation and, only participates in intramolecular pi-stacking interactions with the, benzimidazole ring. These results explain the flat SAR for substitutions, on both rings and the reason why unsubstituted moieties were selected as, candidates. Finally, substituents ortho to the IZD heterocycle on the aryl, ring of the IZD-phenyl moiety bind in a small narrow site adjacent to the, primary phosphate binding pocket. The crystal structure of an o-chloro, derivative reveals that chlorine interacts extensively with residues in, the small site. The structural insights that have led to the discovery of, potent benzimidazole aryl sulfonamide o-substituted derivatives are, discussed in detail.

2CNF is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG and F32 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Protein-tyrosine-phosphatase Protein-tyrosine-phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.48 3.1.3.48] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2CNF OCA].  

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