Pw. Swaan et al., Mapping the binding site of the small intestinal peptide carrier (PepT1) using comparative molecular field analysis, RECEPT CHAN, 6(3), 1998, pp. 189
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.