Three-dimensional quantitative structure-activity relationship analyses of beta-lactam antibiotics and tripeptides as substrates of the mammalian H+/peptide cotransporter PEPT1.
Annegret Biegel, Sabine Gebauer, Bianka Hartrodt, Matthias Brandsch, Klaus Neubert, Iris Thondorf
Index: J. Med. Chem. 48 , 4410-9, (2005)
Full Text: HTML
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.
Related Compounds
Related Articles:
Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.
2009-02-12
[Nature 457(7231) , 910-4, (2009)]
2014-09-01
[Antimicrob. Agents Chemother. 58(9) , 5191-201, (2014)]
2011-02-07
[J. Chem. Phys. 134(5) , 054305, (2011)]
2015-01-27
[Biochemistry 54(3) , 909-31, (2015)]
2010-09-21
[Phys. Chem. Chem. Phys. 12 , 10198-10209, (2010)]