Mapping the binding site of the small intestinal peptide carrier (PepT1) using comparative molecular field analysis

The present study was undertaken to examine the relationship between chemic al structure (steric and electrostatic fields) and affinity for the small i ntestinal oligopeptide carrier (PepT1) using comparative molecular field an alysis (CoMFA), a three-dimensional approach towards building quantitative structure-activity relationships. Various biological activity parameters (K -t, J(max), P-c) and molecular descriptors (CoMFA fields, isobutylalcohol/w ater distribution coefficients) were examined. The resulting field map prov ides information on the geometry of the binding site cavity and the relativ e weights of various properties in different site pockets for each of the s ubstrates considered. The results indicate that carrier permeability (P-c), calculated as the ratio of the half-maximal concentration (K-t) and the ma ximal carrier flux (J(max)), is sensitive to composition, size and hydropho bicity of the ligands. The best model obtained showed a high correlation be tween the carrier permeability (P-c) and the steric (76.3% contribution) an d electrostatic (23.7% contribution) molecular fields with a cross-validate d r(2) (q(2)) of 0.754. The model fitted the experimental data with a corre lation coefficient of 0.993 and a standard error of 0.041, while the regres sion line between experimental and calculated P-c, had a slope of 0.994 wit h an intercept of 0.009. These results lead to a better understanding of th e molecular requirements for optimal drug-carrier interactions with the int estinal peptide transporter and offers a useful visual aid for designing ne w potentially interesting structures with affinity for the oligopeptide tra nsporter PepT1.