title: Molecular determinants of recognition for the intestinal peptide carrier.
abstract: Computer-aided conformational analysis was used to characterize the pharmacophore for the intestinal peptide carrier. The active analog approach to pharmacophore building was applied as implemented in the SYBYL software package. Conformational analysis and MOPAC calculations were used to determine the lowest energy conformation of carrier substrates, as well as the conformations of compounds that displayed a common pharmacophoric geometry (i.e., inhibitors and inactive structural analogs). A pharmacophore map was calculated, and based on structural mutualities and functional topology, three substrate groups were suggested: compounds that bind to the transporter and are transferred across the membrane; compounds that show affinity for the peptide carrier (i.e., known to inhibit transport of substrates) but are not transferred across the membrane; and compounds that contain the pharmacophoric geometry but show no affinity for the carrier. Affinity for the peptide transporter can be diminished or abolished in either of three ways: esterification of the free carboxylic acid moiety; introduction of a second negative group; and intramolecular steric hindrance of the free carboxylic acid by either side chains with a positively charged nitrogen function or groups capable of hydrogen bond formation.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences, University of Utrecht, The Netherlands.
authors.forename: P W
authors.initials: PW
authors.lastname: Swaan
authors.forename: J J
authors.initials: JJ
authors.lastname: Tukker
mesh_terms: D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D002511:Cephalosporins / Q000737:chemistry; D003198:Computer Simulation; D007422:Intestines / Q000737:chemistry*; D008956:Models, Chemical; D010406:Penicillins / Q000737:chemistry
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002352:Carrier Proteins; D002511:Cephalosporins; D010406:Penicillins