A 3-DIMENSIONAL RECEPTOR MODEL FOR ISOVANILLIC SWEET DERIVATIVES

Using pseudoreceptor modelling, we have derived a three-dimensional bi nding-site model for the structurally uncharacterised sweet-taste rece ptor. The receptor model was derived based on 17 sweet compounds of th e isovanillyl class (4-methoxy-3-hydroxybenzyl) as the training set an d consists of nine key amino-acid residues embedded in a hydrophobic r eceptor cavity. The underlying technology (software PrGen) allows for a dynamical treatment of the ligand-receptor complex (ligand equilibra tion and Monte-Carlo scanning of receptor space) as well as for recept or-mediated Ligand alignment. Free energies of ligand binding are esti mated based on ligand-receptor interactions, ligand desolvation energy ,change of ligand internal energy and change of ligand entropy upon re ceptor binding. The validity of the receptor model has been assessed b y using a test set of eight isovanillyl sweet compounds different from the training set, For these ligands, the obtained binding-site surrog ate is capable of predicting free energies of ligand binding, Delta G degrees, 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 fa ctor of 18.