Structural requirements for the substrates of the H+/peptide cotransporter PEPT2 determined by three-dimensional quantitative structure-activity relationship analysis

Abstract

The renal type H(+)/peptide cotransporter PEPT2 has a substantial influence on the in vivo disposition of dipeptides and tripeptides as well as peptide-like drugs within the body, particularly in kidney, lung, and the brain. The comparative molecular similarity indices analysis (CoMSIA) method was applied to identify those regions in the substrate structures that are responsible for recognition and for differences in affinity. We have developed a comprehensive 3D quantitative structure-activity relationship (3D-QSAR) model based on 83 compounds that is able to explain and predict the binding affinities of new PEPT2 substrates. This 3D-QSAR model possesses a high predictive power (q(2) = 0.755; r(2) = 0.893). An additional 3D-QSAR model based on the same compounds was generated and correlated with affinity data of the intestinal H(+)/peptide cotransporter PEPT1. By comparing the CoMSIA contour plots, differences in selectivity between the intestinal and the renal type peptide carrier become evident.