Molecular modeling of the intestinal bile acid carrier: a comparative molecular field analysis study

A structure-binding activity relationship for the intestinal bile acid transporter has been developed using data from a series of bile acid analogs in a comparative molecular field analysis (CoMFA). The studied compounds consisted of a series of bile acid-peptide conjugates, with modifications at the 24 position of the cholic acid sterol nucleus, and compounds with slight modifications at the 3, 7, and 12 positions. For the CoMFA study, these compounds were divided into a training set and a test set, comprising 25 and 5 molecules, respectively. The best three-dimensional quantitative structure-activity relationship model found rationalizes the steric and electrostatic factors which modulate affinity to the bile acid carrier with a cross-validated, conventional and predictive r2 of 0.63, 0.96, and 0.69, respectively, indicating a good predictive model for carrier affinity. Binding is facilitated by positioning an electronegative moiety at the 24-27 position, and also by steric bulk at the end of the side chain. The model suggests substitutions at positions 3, 7, 12, and 24 that could lead to new substrates with reasonable affinity for the carrier.