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

Andersen, Rikke; Jørgensen, Flemming Steen; Olsen, Lars; Våbenø, Jon; Thorn, Karina; Nielsen, Carsten Uhd; Steffansen, Bente

doi:10.1007/s11095-006-9462-y

Cited by 17 publications

(23 citation statements)

References 32 publications

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“…Comparing the present model with the QSAR model developed by Andersen et al employing VolSurf descriptors and with the VolSurf part of the model created by Larsen et al, the overall picture is similar (16,17). Binding is a prerequisite for transport which the resemblance between the affinity and translocation models support.…”

Section: Modelling Of Structure-translocation Relationship Of Tripeptsupporting

confidence: 63%

“…With the aid of VolSurf descriptors, it has been possible to model the relationship between binding and structure of hPEPT1 ligands (16,17). The present study is the first evidence for the VolSurf descriptors being descriptive of the more complicated process of translocation via hPEPT1.…”

Section: Modelling Of Structure-translocation Relationship Of Tripeptmentioning

confidence: 66%

“…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). Recently, Larsen et al published a model using hierarchical projections to latent structures by means of partial least square (PLS) modelling and several alignment independent descriptors (17).…”

Section: Introductionmentioning

confidence: 99%

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

Omkvist

Larsen

Nielsen

et al. 2010

AAPS J

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Abstract. The human intestinal proton-coupled peptide transporter, hPEPT1 (SLC15A1), has been identified as an absorptive transporter for both drug substances and prodrugs. An understanding of the prerequisites for transport has so far been obtained from models based on competition experiments. These models have limited value for predicting substrate translocation via hPEPT1. The aim of the present study was to investigate the requirements for translocation via hPEPT1. A set of 55 tripeptides was selected from a principal component analysis based on VolSurf descriptors using a statistical design. The majority of theses tripeptides have not previously been investigated. Translocation of the tripeptides via hPEPT1 was determined in a MDCK/hPEPT1 cell-based translocation assay measuring substrateinduced changes in fluorescence of a membrane potential-sensitive probe. Affinities for hPEPT1 of relevant tripeptides were determined by competition studies with [14 C]Gly-Sar in MDCK/hPEPT1 cells. Forty tripeptides were found to be substrates for hPEPT1, having K m app values in the range 0.4-28 mM. Eight tripeptides were not able to cause a substrate-induced change in fluorescence in the translocation assay and seven tripeptides interacted with the probe itself. The conformationally restricted tripeptide Met-Pro-Pro was identified as a novel high-affinity inhibitor of hPEPT1. We also discovered the first tripeptide (Asp-Ile-Arg) that was neither a substrate nor an inhibitor of hPEPT1. To rationalise the requirements for transport, a quantitative structure-activity relationship model correlating K m app values with VolSurf descriptors was constructed. This is, to our knowledge, the first predictive model for the translocation of tripeptides via hPEPT1.

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Section: Modelling Of Structure-translocation Relationship Of Tripeptsupporting

confidence: 63%

Section: Modelling Of Structure-translocation Relationship Of Tripeptmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

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

Omkvist

Larsen

Nielsen

et al. 2010

AAPS J

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“…A previous study has shown the value of VolSurf descriptors to identify and rate structural features in tripeptides that are significant for their affinity to hPEPT1. [15] The VolSurf model takes into account descriptors, like molecular size and hydrophilic and hydrophobic properties, by applying GRID 3D molecular interaction fields (MIFs), and energy calculations of the interaction energy between the ligand and different probes. VolSurf descriptors for the 14, Nterminal amino acid substituted tripeptides shown in Table 1 were superimposed on the data set representing all possible 8000 proteinogenic tripeptides using the probes H 2 O, DRY, and O ( Figure 1).…”

Section: Structural Design Strategymentioning

confidence: 99%

“…[15] Increase in the first principal component mainly reflects a decrease in the polarity of the peptide. Decrease in the second principal component predominantly reflects an increase in molecular weight.…”

Section: Structural Design Strategymentioning

confidence: 99%

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

et al. 2007

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The human intestinal proton coupled di/tri-peptide transporter hPEPT1 promotes the oral bioavailability of several drug compounds. The strategy behind the present work is that by linking a suitable di- or tripeptidic promoiety to a drug substance, by a hydrolysable ester bond, it may give rise to a prodrug that targets hPEPT1. 29 tripeptides were designed based on known structural requirements for substrates binding hPEPT1. Serine, homoserine, or threonine was incorporated in the tripeptide as hydroxy group donors in order for them to be linked to carboxylic drug substances. Optimisation of the promoiety included a study of 14 unnatural tripeptides whose diversity was expressed by VolSurf descriptors. A total of 29 tripeptides was synthesised by solid phase peptide synthesis and a standard Fmoc protocol. The affinity of the tripeptides to hPEPT1 was determined by measuring the inhibition of [(14)C]Gly-Sar in mature Caco-2 cell monolayers which resulted in K(i) values ranging from 0.22 to 25 mM or above. Translocation through the intestinal membrane, mediated by hPEPT1, was measured by recording the membrane potential relative to that induced by the known substrate Gly-Sar. The change in membrane potential is caused by influx of protons due to the co-transport of substrates and protons by hPEPT1 and is, as such, an indication of translocation. A K(i) value of 0.30 mM combined with efficient translocation indicated that H-Phe-Ser-Ala-OH is a suitable lead promoiety for targeted hPEPT1 prodrug design.

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Transporters in the Gastrointestinal Tract

Anderle

Nielsen

2008

Methods and Principles in Medicinal Chemistry

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

Cited by 17 publications

References 32 publications

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

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

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

Transporters in the Gastrointestinal Tract

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