CONFORMATION ACTIVITY RELATIONSHIP OF SWEET MOLECULES - COMPARISON OF ASPARTAME AND NAPHTHIMIDAZOLESULFONIC ACIDS

The shape of the active site of the receptor for sweet molecules was previously defined on the basis of a combination of both rigid (saccharins) and flexible (aspartame) molds. In this paper, the sweetness receptor is refined with use of the shapes of 3-anilino-2-styryl-3H-naphtho[1,2-d]imidazolesulfonate (sweet) and of 3-anilino-2-phenyl-3/H-naphtho[1,2-d]imidazolesulfonate (tasteless), two large and almost completely rigid tastants. The mimimum-energy conformations of the flexible portions of these tastants have been determined by using a detailed conformational analysis based on ab initio calculations. The refined receptor site is still consistent with all previously examined sweet molecules. In order to unequivocally assign the prochiral β-CH2protons of the Phe moiety of aspartame, (2S,3S)-[2H]-α-L-Asp-L-PheoMe was synthesized and examined by 500-MHz 1H NMR spectroscopy. The results indicate that the minimum-energy conformation for aspartame in water, DMSO-d6, and CDCl3(as a crown ether complex) is different from that originally proposed (FIIDIIinstead of FIDII, according to a notation referred to the side chains). Although this conformation is not directly consistent with the shape of the sweet receptor, the interconversion of FIIDIIto FIDIIwas found to require only 1 kcal/mol. Furthermore, a 120-ps molecular dynamics simulation in vacuo confirms the high flexibility of aspartame and the accessibility of the FjDn conformer whose topology is fully consistent with our model. © 1990, American Chemical Society. All rights reserved.