Edge-to-face CH/pi interaction between ligand Phe-phenyl and receptor aromatic group in the thrombin receptor activation

In the ligand/receptor interaction, the side chain phenyl group of phenylal anine (Phe) is involved in a so-called hydrophobic interaction, in which th e]Phe-phenyl group functions as a pi element or merely as a hydrophobic ele ment. The thrombin receptor-tethered ligand SFLLRNP consists of the Phe-2 r esidue essential for receptor activation, In order to explore the molecular characteristics of this Phe-2-phenyl group, a complete set of S/Phe/LLRNP peptides comprising six different difluorophenylalanine isomers [(F-2)Phe] was newly synthesized and assayed to evaluate their ability to induce the a ggregation of human platelets, The assay results clarified several importan t structural elements to conclude that Phe-2-phenyl of S/Phe/LLRNP is in th e edge-to-face CH/pi Interaction with the receptor aromatic group, utilizin g the Phe-phenyl edge along with adjacent benzene hydrogens at positions (2 -3) or (5-6). It was also found that the fluorine atom at position 4 increa ses the acidity of the hydrogen mainly at its ortho position, resulting in a reinforcement; of the CH/pi interaction and thus in an enhancement of bio logical activity. The H-->F replacement in the benzene ring was found to pr ovide an effective structural examination to the Phe residue; i.e., to iden tify the hydrogens in the CH/pi interaction, and to strengthen the CH/pi in teraction.