Three-dimensional quantitative structure-activity relationship analyses of beta-lactam antibiotics and tripeptides as substrates of the mammalian H+/peptide cotransporter PEPT1.
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.
Biegel
Annegret
A
Institute of Biochemistry, Department of Biochemistry/Biotechnology, Martin-Luther-University Halle-Wittenberg, D-06099 Halle, Germany.
Gebauer
Sabine
S
Hartrodt
Bianka
B
Brandsch
Matthias
M
Neubert
Klaus
K
Thondorf
Iris
I
D000818:Animals; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008322:Mammals; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000074011:Peptide Transporter 1; D021281:Quantitative Structure-Activity Relationship; D013379:Substrate Specificity; D027981:Symporters / Q000378:metabolism*; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics
D004151:Dipeptides; D009842:Oligopeptides; D000074011:Peptide Transporter 1; D027981:Symporters; D047090:beta-Lactams