PT  - JOURNAL ARTICLE
AU  - Françoise Hervé
AU  - Giulia Caron
AU  - Jean-Claude Duché
AU  - Patrick Gaillard
AU  - Noorsaadah Abd. Rahman
AU  - Anna Tsantili-Kakoulidou
AU  - Pierre-Alain Carrupt
AU  - Philippe d’Athis
AU  - Jean-Paul Tillement
AU  - Bernard Testa
TI  - Ligand Specificity of the Genetic Variants of Human α<sub>1</sub>-Acid Glycoprotein: Generation of a Three-Dimensional Quantitative Structure-Activity Relationship Model for Drug Binding to the A Variant
AID  - 10.1124/mol.54.1.129
DP  - 1998 Jul 01
TA  - Molecular Pharmacology
PG  - 129--138
VI  - 54
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/54/1/129.short
4100  - http://molpharm.aspetjournals.org/content/54/1/129.full
SO  - Mol Pharmacol1998 Jul 01; 54
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.