A MOLECULAR-DYNAMICS APPROACH TO RECEPTOR MAPPING - APPLICATION TO THE 5HT(3) AND BETA(2)-ADRENERGIC RECEPTORS

A molecular dynamics-based approach to receptor mapping is proposed, b ased on the method of Rizzi (Rizzi, J. P.; et al. J. Med. Chem. 1990, 33, 2721). In Rizzi's method, the interaction energy between a series of drug molecules and probe atoms (which mimic functional groups on th e receptor, such as hydrogen bond donors) was calculated. These intera ctions were calculated on a three-dimensional grid within a molecular mechanics framework, and the minima in the grid were associated with t he binding site on the receptor. In this extension, dummy atoms, bonde d to the drug with appropriate molecular mechanics parameters, were pl aced at these minima. The distances between the dummy atom sites were monitored during molecular dynamics simulations and plotted as distanc e distribution functions. Important distances within the receptor beca me apparent, as drugs with a common mode of binding share similar peak s in the distance distribution functions. In the case of specific 5HT( 3) ligands, the important donor-acceptor distance within the receptor has a range of ca. 7.9 - 8.9 Angstrom. In the case of specific beta(2) -adrenergic ligands, the important donor-acceptor distances within the receptor Lie between ca. 7 - 9 Angstrom and between 8 and 10 Angstrom . These distance distribution functions were used to assess three diff erent models of the beta(2)-adrenergic G-protein-coupled receptor. The comparison of the distance distribution functions for the simulation with the actual donor-acceptor distances in the receptor models sugges ted that two of the three receptor models were much more consistent: w ith the receptor-mapping studies. These receptor-mapping studies gave support for the use of rhodopsin, rather than the bacteriorhodopsin te mplate, for modeling G-protein-coupled receptors but also sounded a wa rning that agreement with binding data from site-directed mutagenesis experiments does not necessarily validate a receptor model.