LIGAND SPECIFICITY OF THE GENETIC-VARIANTS OF HUMAN ALPHA(1)-ACID GLYCOPROTEIN - GENERATION OF A 3-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP MODEL FOR DRUG-BINDING TO THE A VARIANT

Human alpha(1)-acid glycoprotein (AAG) is a mixture of at least two ge netic variants: the A variant and the F1 and/or S variant or variants, which are encoded by two different genes. In a continuation of previo us studies indicating specific drug transport roles for each AAG varia nt 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 chemi cally diverse drugs and (2) to obtain meaningful 3D-QSARs for each bin ding site. Affinities were obtained by displacement experiments, leadi ng to qualitative indications about binding site characteristics. In p articular, drugs binding selectively to the A variant displayed some c ommon structural features, but this was not seen for the F1S variants . Three-dimensional QSAR analyses using the CoMFA method yielded a ste ric model for binding to the A variant, from which a simplified haptop horic model was derived. In contrast, no statistically sound model was found for the F1S variants, possibly due (among other reasons) to an insufficient number of high affinity ligands in the set.