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1.
Eur J Pharm Sci ; 32(1): 69-76, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17644326

RESUMO

The H(+)/peptide cotransporters PEPT1 and PEPT2 have gained considerable interest in pharmaceutical sciences as routes for drug delivery. It is, therefore, of interest to develop uncommon artificial substrates for the two carriers. This study was initiated to investigate the binding affinity of 2-aminothiazole-4-acetic acid (ATAA) conjugates with amino acids to PEPT1 and PEPT2. The 2-aminothiazole-4-acetic acid derivatives have been synthesised and tested for their affinity to PEPT1 and PEPT2. The K(i) values were compared with in silico predicted values from CoMSIA models. C-terminal ATAA-Xaa conjugates proved to be low to medium inhibitors of the [(14)C]Gly-Sar uptake at both carrier systems whereas N-terminal Xaa-ATAA conjugates exhibited medium to high affinity. A promising candidate for further functionalisation is Val-ATAA which shows extraordinary high affinity to PEPT1.


Assuntos
Cefalosporinas/metabolismo , Simportadores/metabolismo , Aminoácidos/química , Aminoácidos/metabolismo , Aminoácidos/farmacocinética , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacocinética , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Células CACO-2 , Ceftibuteno , Células Cultivadas , Cefalosporinas/química , Cefalosporinas/farmacocinética , Dipeptídeos/química , Dipeptídeos/metabolismo , Dipeptídeos/farmacocinética , Humanos , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/metabolismo , Cinética , Modelos Moleculares , Estrutura Molecular , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacocinética , Transportador 1 de Peptídeos , Ligação Proteica , Ratos , Simportadores/antagonistas & inibidores , Simportadores/fisiologia
2.
J Med Chem ; 49(14): 4286-96, 2006 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-16821788

RESUMO

The renal type H(+)/peptide cotransporter PEPT2 has a substantial influence on the in vivo disposition of dipeptides and tripeptides as well as peptide-like drugs within the body, particularly in kidney, lung, and the brain. The comparative molecular similarity indices analysis (CoMSIA) method was applied to identify those regions in the substrate structures that are responsible for recognition and for differences in affinity. We have developed a comprehensive 3D quantitative structure-activity relationship (3D-QSAR) model based on 83 compounds that is able to explain and predict the binding affinities of new PEPT2 substrates. This 3D-QSAR model possesses a high predictive power (q(2) = 0.755; r(2) = 0.893). An additional 3D-QSAR model based on the same compounds was generated and correlated with affinity data of the intestinal H(+)/peptide cotransporter PEPT1. By comparing the CoMSIA contour plots, differences in selectivity between the intestinal and the renal type peptide carrier become evident.


Assuntos
Antibacterianos/química , Oligopeptídeos/química , Relação Quantitativa Estrutura-Atividade , Simportadores/química , beta-Lactamas/química , Cefalosporinas/química , Dipeptídeos/química , Modelos Moleculares , Conformação Molecular , Penicilinas/química , Transportador 1 de Peptídeos , Ligação Proteica
3.
J Med Chem ; 48(13): 4410-9, 2005 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-15974593

RESUMO

The utilization of the membrane transport protein PEPT1 as a drug delivery system is a promising strategy to enhance the oral bioavailability of drugs. Since very little is known about the substrate binding site of PEPT1, computational methods are a meaningful tool to gain a more detailed insight into the structural requirements for substrates. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using the comparative molecular similarity indices analysis (CoMSIA) method were performed on a training set of 98 compounds. Affinity constants of beta-lactam antibiotics and tripeptides were determined at Caco-2 cells. A statistically reliable model of high predictive power was obtained (q(2) = 0.828, r(2) = 0.937). The results derived from CoMSIA were graphically interpreted using different field contribution maps. We identified those regions which are crucial for the interaction between peptidomimetics and PEPT1. The new 3D-QSAR model was used to design a new druglike compound mimicking a dipeptide. The predicted K(i) value was confirmed experimentally.


Assuntos
Oligopeptídeos/síntese química , Simportadores/metabolismo , beta-Lactamas/síntese química , Animais , Linhagem Celular Tumoral , Dipeptídeos/metabolismo , Desenho de Fármacos , Humanos , Mamíferos , Modelos Moleculares , Oligopeptídeos/química , Oligopeptídeos/farmacocinética , Transportador 1 de Peptídeos , Relação Quantitativa Estrutura-Atividade , Especificidade por Substrato , beta-Lactamas/química , beta-Lactamas/farmacocinética
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