Abstract
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.
Footnotes
- Received August 1, 1997.
- Accepted March 16, 1998.
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Send reprint requests to: Prof. Bernard Testa, School of Pharmacy, BEP, University of Lausanne, CH-1015 Lausanne, Switzerland. E-mail: bernard.testa{at}ict.unil.ch
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↵1 Current affiliation: Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia.
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B.T. and P.A.C. are indebted to the Swiss National Science Foundation for support. F.H., J.C.D., and J.P.T. are indebted to the Ministère de l’Education Nationale (EA 427) and to the Réseau de Pharmacologie Clinique for support. N.A.R. acknowledges receipt of a JWT Jones Travelling Fellowship given by the Royal Society of Chemistry. A.T.K. is indebted to the Foundation Herbette (University of Lausanne) for a travel grant. F.H. and G.C. contributed equally to this study.
- The American Society for Pharmacology and Experimental Therapeutics
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