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Three-dimensional quantitative structure-activity relationship analyses of peptide substrates of the mammalian H+/peptide cotransporter PEPT1.
J Med Chem. 2003 Dec 18; 46(26):5725-34.JM

Abstract

The utilization of the carrier protein PEPT1 for the absorption of peptidomimetic drug molecules is a promising strategy for oral drug administration and increasing bioavailability. In the absence of structural information on the binding mode of substrates to PEPT1, a computational study was conducted to explore the structural requirements for substrates and to derive a predictive model that may be used for the design of novel orally active drugs. A comparative molecular field analysis (CoMFA) and a comparative molecular similarity indices analysis (CoMSIA) were performed on a series of 79 dipeptide-type substrates for which affinity data had been collected in a single test system under the same conditions. These studies produced models with conventional r(2) and cross-validated coefficient (q(2)) values of 0.901 and 0.642 for CoMFA and 0.913 and 0.776 for CoMSIA. The models were validated by an external test set of 19 dipeptides and dipeptide derivatives. CoMSIA contour maps were used to identify the recognition elements that are relevant for the binding of PEPT1 substrates. The 3D QSAR models provide an insight in the interactions between substrates and PEPT1 on the molecular level and allow the prediction of affinity constants of new compounds.

Authors+Show Affiliations

Gebauer S
Institute of Biochemistry, Department of Biochemistry/Biotechnology, and Biozentrum, Martin-Luther-University Halle-Wittenberg, D-06099 Halle, Germany.
Knütter I
No affiliation info available
Hartrodt B
No affiliation info available
Brandsch M
No affiliation info available
Neubert K
No affiliation info available
Thondorf I
No affiliation info available

MeSH

Carrier ProteinsDipeptidesDrug DesignLigandsModels, MolecularMolecular ConformationPeptide Transporter 1Protein BindingQuantitative Structure-Activity RelationshipSymporters

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14667225

Citation

Gebauer, Sabine, et al. "Three-dimensional Quantitative Structure-activity Relationship Analyses of Peptide Substrates of the Mammalian H+/peptide Cotransporter PEPT1." Journal of Medicinal Chemistry, vol. 46, no. 26, 2003, pp. 5725-34.
Gebauer S, Knütter I, Hartrodt B, et al. Three-dimensional quantitative structure-activity relationship analyses of peptide substrates of the mammalian H+/peptide cotransporter PEPT1. J Med Chem. 2003;46(26):5725-34.
Gebauer, S., Knütter, I., Hartrodt, B., Brandsch, M., Neubert, K., & Thondorf, I. (2003). Three-dimensional quantitative structure-activity relationship analyses of peptide substrates of the mammalian H+/peptide cotransporter PEPT1. Journal of Medicinal Chemistry, 46(26), 5725-34.
Gebauer S, et al. Three-dimensional Quantitative Structure-activity Relationship Analyses of Peptide Substrates of the Mammalian H+/peptide Cotransporter PEPT1. J Med Chem. 2003 Dec 18;46(26):5725-34. PubMed PMID: 14667225.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Three-dimensional quantitative structure-activity relationship analyses of peptide substrates of the mammalian H+/peptide cotransporter PEPT1. AU - Gebauer,Sabine, AU - Knütter,Ilka, AU - Hartrodt,Bianka, AU - Brandsch,Matthias, AU - Neubert,Klaus, AU - Thondorf,Iris, PY - 2003/12/12/pubmed PY - 2004/1/21/medline PY - 2003/12/12/entrez SP - 5725 EP - 34 JF - Journal of medicinal chemistry JO - J Med Chem VL - 46 IS - 26 N2 - The utilization of the carrier protein PEPT1 for the absorption of peptidomimetic drug molecules is a promising strategy for oral drug administration and increasing bioavailability. In the absence of structural information on the binding mode of substrates to PEPT1, a computational study was conducted to explore the structural requirements for substrates and to derive a predictive model that may be used for the design of novel orally active drugs. A comparative molecular field analysis (CoMFA) and a comparative molecular similarity indices analysis (CoMSIA) were performed on a series of 79 dipeptide-type substrates for which affinity data had been collected in a single test system under the same conditions. These studies produced models with conventional r(2) and cross-validated coefficient (q(2)) values of 0.901 and 0.642 for CoMFA and 0.913 and 0.776 for CoMSIA. The models were validated by an external test set of 19 dipeptides and dipeptide derivatives. CoMSIA contour maps were used to identify the recognition elements that are relevant for the binding of PEPT1 substrates. The 3D QSAR models provide an insight in the interactions between substrates and PEPT1 on the molecular level and allow the prediction of affinity constants of new compounds. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/14667225/Three_dimensional_quantitative_structure_activity_relationship_analyses_of_peptide_substrates_of_the_mammalian_H+/peptide_cotransporter_PEPT1_ DB - PRIME DP - Unbound Medicine ER -