RT Journal Article SR Electronic T1 Ligand Specificity of the Genetic Variants of Human α1-Acid Glycoprotein: Generation of a Three-Dimensional Quantitative Structure-Activity Relationship Model for Drug Binding to the A Variant JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 129 OP 138 DO 10.1124/mol.54.1.129 VO 54 IS 1 A1 Françoise Hervé A1 Giulia Caron A1 Jean-Claude Duché A1 Patrick Gaillard A1 Noorsaadah Abd. Rahman A1 Anna Tsantili-Kakoulidou A1 Pierre-Alain Carrupt A1 Philippe d’Athis A1 Jean-Paul Tillement A1 Bernard Testa YR 1998 UL http://molpharm.aspetjournals.org/content/54/1/129.abstract AB Human α1-acid glycoprotein (AAG) is a mixture of at least two genetic variants: the A variant and the F1 and/or S variant or variants, which are encoded by two different genes. In a continuation of previous studies indicating specific drug transport roles for each AAG variant according to its separate genetic origin, this work was designed to (1) determine the affinities of the two main gene products of AAG (i.e., the A variant and a mixture of the F1 and S variants) for 35 chemically diverse drugs and (2) to obtain meaningful 3D-QSARs for each binding site. Affinities were obtained by displacement experiments, leading to qualitative indications about binding site characteristics. In particular, drugs binding selectively to the A variant displayed some common structural features, but this was not seen for the F1*S variants. Three-dimensional QSAR analyses using the CoMFA method yielded a steric model for binding to the A variant, from which a simplified haptophoric model was derived. In contrast, no statistically sound model was found for the F1*S variants, possibly due (among other reasons) to an insufficient number of high affinity ligands in the set.