RESUMO
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.
Assuntos
Inibidores da Dipeptidil Peptidase IV , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Dipeptidil Peptidase 4/sangue , Avaliação Pré-Clínica de Medicamentos , Ligação de Hidrogênio , Masculino , Modelos Moleculares , Conformação Molecular , Inibidores de Proteases/química , Ratos , Ratos Wistar , Espectrometria de FluorescênciaRESUMO
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.