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Development of a QSAR Model for Binding of Tripeptides and Tripeptidomimetics to the Human Intestinal Di-/Tripeptide Transporter hPEPT1

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Purpose

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.

Methods

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.

Results

The K i -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.

Conclusion

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.

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Abbreviations

Ψ:

N- methyl amide bond isostere Ψ [CONCH3]

3D-QSAR:

three-dimensional quantitative structure– activity relationship

CoMSIA:

comparative molecular similarity indices analysis

PCA:

principal component analysis

PLS:

partial least square of latent variables

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Acknowledgments

The Danish Medicinal Council supported this work (project grant 22-03-0274). Zealand Pharma A/S financially supported this work via the Drug Research Academy, Danish University of Pharmaceutical Sciences, Copenhagen, Denmark. Partial funding was obtained from the BioSim workpackage 15 funded by the European Commission (BioSim NoE LSH-CT-005137). The HPLC system was cofunded by the Hørslev Foundation. We appreciate the support by Tripos Associates and Gabriele Cruciani regarding the access to Sybyl and VolSurf. The technical assistance of Bettina Dinitzen and Susanne Nørskov Sørensen is highly appreciated.

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Authors and Affiliations

  1. Molecular Biopharmaceutics, The Danish University of Pharmaceutical Sciences, 2-Universitetsparken, DK-2100, Copenhagen, Denmark

    Rikke Andersen, Jon Våbenø, Carsten Uhd Nielsen & Bente Steffansen

  2. Biostructural Research, The Danish University of Pharmaceutical Sciences, 2-Universitetsparken, DK-2100, Copenhagen, Denmark

    Flemming Steen Jørgensen & Lars Olsen

  3. Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, 2-Universitetsparken, DK-2100, Copenhagen, Denmark

    Karina Thorn

  4. Center for Computational Biology, Washington University School of Medicine, St. Louis, Missouri, USA

    Jon Våbenø

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  1. Rikke Andersen
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  2. Flemming Steen Jørgensen
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Correspondence to Rikke Andersen.

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Andersen, R., Jørgensen, F.S., Olsen, L. et al. Development of a QSAR Model for Binding of Tripeptides and Tripeptidomimetics to the Human Intestinal Di-/Tripeptide Transporter hPEPT1. Pharm Res 23, 483–492 (2006). https://doi.org/10.1007/s11095-006-9462-y

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