A three-dimensional receptor model for isovanillic sweet derivatives

Abstract

Using pseudoreceptor modelling, we have derived a three-dimensional binding-site model for the structurally uncharacterised sweet-taste receptor. The receptor model was derived based on 17 sweet compounds of the isovanillyl class (4-methoxy-3-hydroxybenzyl) as the training set and consists of nine key amino-acid residues embedded in a hydrophobic receptor cavity. The underlying technology (software PrGen) allows for a dynamical treatment of the ligand–receptor complex (ligand equilibration and Monte-Carlo scanning of receptor space) as well as for receptor-mediated ligand alignment. Free energies of ligand binding are estimated based on ligand–receptor interactions, ligand desolvation energy, change of ligand internal energy and change of ligand entropy upon receptor binding.

The validity of the receptor model has been assessed by using a test set of eight isovanillyl sweet compounds different from the training set. For these ligands, the obtained binding-site surrogate is capable of predicting free energies of ligand binding, ΔG°, to within 0.99 kcal mol^–1 (rms) of their experimental value, corresponding to an uncertainty in the sweetness of a factor of 5.5. Maximal individual errors of predicted sweetnesses do not exceed a factor of 18.