RESUMEN
A series of non-covalent inhibitors of the serine protease dipeptidyl peptidase IV (DPP-IV) were found to adopt a U-shaped binding conformation in X-ray co-crystallization studies. Remarkably, Tyr547 undergoes a 70 degrees side-chain rotation to accommodate the inhibitor and allows access to a previously unexposed area of the protein backbone for hydrogen bonding.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Dipeptidil Peptidasa 4/sangre , Evaluación Preclínica de Medicamentos , Enlace de Hidrógeno , Masculino , Modelos Moleculares , Conformación Molecular , Inhibidores de Proteasas/química , Ratas , Ratas Wistar , Espectrometría de FluorescenciaRESUMEN
A series of growth hormone secretagogues (GHSs) based on 2,3-dihydroisothiazole has been synthesized in the search for a potential treatment of growth hormone deficiency or frailty in the elderly. This paper describes the evaluation of the SAR of the benzyl-D-Ser-aminoisobutyric acid dipeptide fragment. Introduction of substituents in the peptide backbone and in the phenyl ring has been investigated, as well as replacements for the benzyl group and for the AIB residue. A number of modifications resulted in enhanced potency over the parent benzyl-D-Ser-AIB derivative.
