Molecular recognition mechanisms of vanillin and high-throughput screening of its analogs based on olfactory receptors

Abstract

The interaction mechanisms between vanillin and olfactory receptors were studied by computational chemistry approaches. Results showed that 10 receptors exhibited different affinities for vanillin (−4.992∼-6.518 kcal/mol). Residues Arg286 (81%, OR2G2), His154 (78%, OR10G4; 62%, OR10G7), His104 (72%, OR10G4), Gly203 (57%, OR1L3), Val182 (58%, OR2J2), and Glu182 (51%, OR5AC2) with high frequencies particularly contributed to vanillin recognition. Hydrogen bonding coupled with hydrophobic interactions were the key forces of binding, and the hydroxyl group of vanillin was essential for its stability in olfactory receptors. Odorants 2,6-dimethoxy-4-methylphenol (2#), vanillyl alcohol (9#), 1-(5-methyl-2-thienyl)ethan-1-one (29#), and 3-acetylpyridine (37#) were identified as vanillin analogs based on comparative molecular field analysis, among them, 9# matched well (0.80–0.91, overall similarity) with the molecular fields of the nine template ligands. Sensory analysis showed that the addition of 2#, 9#, and 37# effectively increased the correct detection probability of vanillin at low concentrations and decreased the vanillin detection threshold. The obtained results contribute to better understanding of vanillin perception and screening of its analogs.