Three-Dimensional Quantitative Structure−Activity Relationship Analyses of β-Lactam Antibiotics and Tripeptides as Substrates of the Mammalian H⁺/Peptide Cotransporter PEPT1

Abstract

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.

A Quantitative Structure–Activity Relationship for Translocation of Tripeptides via the Human Proton-Coupled Peptide Transporter, hPEPT1 (SLC15A1)

“…This implies that the conformation adapted by the semi-rigid Met-Pro-Pro molecule was favourable for binding to hPEPT1 but unfavourable for translocation. Biegel et al have shown that Ile-Pro-Pro and Val-Pro-Pro have affinity constants of 0.28 and 0.06 mM, respectively (14), which was in accordance with X aa -Pro-Pro binding to hPEPT1 with high affinity. Whether these two tripeptides were transported by hPEPT1 was, however, not reported (14).…”

“…Bailey et al reported a template for PEPT1 substrates, which identified four key binding regions in the PEPT1 binding site (13). Gebauer et al created a quantitative structure-activity relationship (QSAR) model on dipeptides, tripeptides and β-lactam antibiotics employing CoMSIA descriptors (14,15). A QSAR model that correlates the binding of tripeptides to hPEPT1 with the alignment independent VolSurf descriptors was reported in 2006 (16).…”

MDCK Cells and Other Cell‐Culture Models of Oral Drug Absorption

“…These transfected models add greatly to our knowledge and understanding of substrate specificity for a specific transporter. Information of substrate specificity can be further incorporated into computational modeling which may aid in the design of better substrate or inhibitor drug molecules to increase the bioavailability (Schwab et al, 2003;Biegel et al, 2005;Ungell, 2004). Structural requirements for only a few transporter systems have been identified like PePT1 (Biegel et al, 2005) and P-gp (Ekins et al, 2002;Schwab et al, 2003;Ungell, 2004).…”

Design, Synthesis, and Evaluation of Tripeptidic Promoieties Targeting the Intestinal Peptide Transporter hPEPT1

“…The effort for unravelling structural elements of the di-/ tripeptides important for binding and translocation by hPEPT1 have resulted in a few quantitative structure-affinity relationship models. [12][13][14][15] It is generally accepted that the transporter has a preference for di-and tripeptides composed of l-configured amino acids with the peptide bonds in a trans-conformation. A free amino group in the N-terminal seems to be important whereas a free carboxylic acid in the C-terminal is not an absolute prerequisite.…”