Identification of the First Low-Molecular-Weight Inhibitors of Matriptase-2
| Autor: | Jürgen Bajorath, Michael Gütschow, Torsten Steinmetzer, Mihiret T. Sisay, Eva Maurer, Marit Stirnberg, Maya Hammami |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Stereochemistry
medicine.medical_treatment Molecular Sequence Data Crystallography X-Ray Cell Line chemistry.chemical_compound Hepcidin Catalytic Domain Drug Discovery medicine Humans Matriptase Amino Acid Sequence Hemochromatosis chemistry.chemical_classification Serine protease Sulfonamides Protease Dipeptide biology Chemistry Serine Endopeptidases Membrane Proteins Dipeptides medicine.disease Small molecule Benzamidines Molecular Weight Enzyme Biochemistry biology.protein Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 53:5523-5535 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm100183e |
| Popis: | As recently discovered, matriptase-2, a type II transmembrane serine protease, plays a crucial role in body iron homeostasis by down-regulating hepcidin expression, which results in increased iron levels. Thus, matriptase-2 represents a novel target for the development of enzyme inhibitors potentially useful for the treatment of systemic iron overload (hemochromatosis). A comparative three-dimensional model of the catalytic domain of matriptase-2 was generated and utilized for structure-based virtual screening in combination with similarity searching and knowledge-based compound design. Two N-protected dipeptide amides containing a 4-amidinobenzylamide as P1 residue (compounds 1 and 3) were identified as the first small molecule inhibitors of matriptase-2 with K(i) values of 170 and 460 nM, respectively. An inhibitor of the closely related protease matriptase (compound 2, K(i) = 220 nM), with more than 50-fold selectivity over matriptase-2, was also identified. |
| Databáze: | OpenAIRE |
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