RELATIVE BINDING ORIENTATIONS OF ADENOSINE-A(1) RECEPTOR LIGANDS - A TEST-CASE FOR DISTRIBUTED MULTIPOLE ANALYSIS IN MEDICINAL CHEMISTRY

The electrostatic properties of adenosine-based agonists and xanthine- based antagonists for the adenosine A(1) receptor were used to assess various proposals for their relative orientation in the unknown bindin g site. The electrostatic properties were calculated from distributed multipole representations of SCF wavefunctions. A range of methods of assessing the electrostatic similarity of the ligands were used in the comparison. One of the methods, comparing the sign of the potential a round the two molecules, gave inconclusive results. The other approach es, however, provided a mutually complementary and consistent picture of the electrostatic similarity and dissimilarity of the molecules in the three proposed relative orientations. This was significantly diffe rent from the results obtained previously with MOPAC AM1 point charges . In the standard model overlay, where the aromatic nitrogen atoms of both agonists and antagonists are in the same position relative to the binding site, the electrostatic potentials are so dissimilar that bin ding to the same receptor site is highly unlikely. Overlaying the N-6- region of adenosine with that near C8 of theophylline (the N-6-C8 mode l) produces the greatest similarity in electrostatic properties for th ese ligands. However, N-6-cyclopentyladenosine (CPA) and 1,3-dipropyl- 8-cyclopentyl-xanthine (DPCPX) show greater electrostatic similarity w hen the aromatic rings are superimposed according to the flipped model , in which the xanthine ring is rotated around its horizontal axis. Th is difference is mainly attributed to the change in conformation of N- 6-substituted adenosines and could result in a different orientation f or theophylline and DPCPX within the receptor binding site. However, i t is more likely that DPCPX also binds according to the N-6-C8 model, as this model gives the best steric overlay and would be favoured by t he lipophilic forces, provided that the binding site residues could ac commodate the different electrostatic properties in the N-6/N7-region. Finally, we have shown that Distributed Multipole Analysis (DMA) offe rs a new, feasible tool for the medicinal chemist, because it provides the use of reliable electrostatic models to determine plausible relat ive binding orientations.