Development of a QSAR Model for Binding of Tripeptides and Tripeptidomimetics to the Human Intestinal Di-/Tripeptide Transporter hPEPT1
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- Andersen, R., Jørgensen, F.S., Olsen, L. et al. Pharm Res (2006) 23: 483. doi:10.1007/s11095-006-9462-y
The aim of this study was to develop a three-dimensional quantitative structure–activity relationship (QSAR) model for binding of tripeptides and tripeptidomimetics to hPEPT1 based on a series of 25 diverse tripeptides.
VolSurf descriptors were generated and correlated with binding affinities by multivariate data analysis. The affinities for hPEPT1 of the tripeptides and tripeptidomimetics were determined experimentally by use of Caco-2 cell monolayers.
The Ki-values of the 25 tripeptides and tripeptidomimetics ranged from 0.15 to 25 mM and the structural diversity of the compounds was described by VolSurf descriptors. A QSAR model that correlated the VolSurf descriptors of the tripeptides with their experimental binding affinity for hPEPT1 was established.
Structural information on tripeptide properties influencing the binding to hPEPT1 was extracted from the QSAR model. This information may contribute to the drug design process of tripeptides and tripeptidomimetics where hPEPT1 is targeted as an absorptive transporter for improvement of intestinal absorption. To our knowledge, this is the first time a correlation between VolSurf descriptors and binding affinities for hPEPT1 has been reported.
Key WordshPEPT1 QSAR tripeptides tripeptidomimetics VolSurf
N- methyl amide bond isostere Ψ [CONCH3]
three-dimensional quantitative structure– activity relationship
comparative molecular similarity indices analysis
principal component analysis
partial least square of latent variables