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

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Abstract

A structure–binding activity relationship for the intestinal bile acidtransporter has been developed using data from a series of bile acid analogsin a comparative molecular field analysis (CoMFA). The studied compoundsconsisted of a series of bile acid–peptide conjugates, withmodifications at the 24 position of the cholic acid sterol nucleus, andcompounds with slight modifications at the 3, 7, and 12 positions. For theCoMFA study, these compounds were divided into a training set and a test set,comprising 25 and 5 molecules, respectively. The best three-dimensionalquantitative structure–activity relationship model found rationalizesthe steric and electrostatic factors which modulate affinity to the bile acidcarrier with a cross-validated, conventional and predictive r2of 0.63, 0.96, and 0.69, respectively, indicating a good predictive model forcarrier affinity. Binding is facilitated by positioning an electronegativemoiety at the 24–27 position, and also by steric bulk at the end of theside chain. The model suggests substitutions at positions 3, 7, 12, and 24that could lead to new substrates with reasonable affinity for the carrier.

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Swaan, P.W., Jr., F.C.S. & Øie, S. Molecular modeling of the intestinal bile acid carrier: A comparative molecular field analysis study. J Comput Aided Mol Des 11, 581–588 (1997). https://doi.org/10.1023/A:1007919704457

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  • DOI: https://doi.org/10.1023/A:1007919704457

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