Exploring of odor blending in odorant mixtures by a pharmacophore approach
Résumé
The first step of odor perception is an interaction between odorants and olfactory receptors (ORs) [1]. It is now accepted that the main strategy used by Humans to perceive thousands of odors results from a combinatorial coding [2]. Moreover, odors we perceived in our environment are mainly the result of mixtures of odorants; however, the processes involved remain poorly understood [3]. In previous studies performed in the CSGA of Dijon[4, 5], the perception of a mixture of specific proportions of ethyl isobutyrate (Et-iB, strawberry-like odor) and ethyl maltol (Et-M, caramel-like odor) was investigated in comparison with a reference (allyl hexanoate, Al-H, pineapple-like odor) chosen to evoke an odor close to the one expected in the mixture. The binary specific mixture of Et-iB and Et-M was judged as more typical of a pineapple odor than the individual components, whereas Al-H constitutes a good pineapple odor reference. Assuming that combinations of activated ORs encode odor qualities and that molecules sharing a same odorant quality possess common structural molecular property [6, 7], our assumption was that molecules sharing strawberry, caramel or pineapple odor should also share several common structural characteristics. We used Common Feature Pharmacophore Generation protocol (Discovery Studio 4.1, Biovia) to generate pharmacophore hypotheses [8]; the maximum number of generated hypothesis for each run was set to 10. In our study, the pharmacophoric features considered are hydrogen bond acceptors (HBA) and hydrophobic regions (HY). On the one hand, pharmacophore generation performed with the three molecules allowed to obtain 10 hypotheses, and the best model is made up of 2 HY and 2 HBA. On the other hand, the best models obtained on each molecule (all conformers in a range 0-20 kcal/mol) are made up of at least 1 HY and 2 HBA. Side-by-side comparisons of pharmacophores reveal inter-features distance commonalities. By performing three tests by mapping of each molecules pair on the pharmacophore of the third molecule, we obtained good fit values for mapping of Et-M and Al-H on Et-iB model (3.9-2.3; the smallest values correspond to the mapping of Et-M conformers) and for mapping of Et-iB and Al-H on Et-M model (2.8-2.5; the smallest values correspond to the mapping of Et-iB conformers). Conversely, none of Et-M conformers and only half of Et-iB conformers map on Al-H model and fit values do not exceed 2. Taken together, these results suggest that a common binding site could exist for the three molecules, and Al-H could also bind on sites of Et-iB and Et-M. This is in good accordance with the schema of combinatorial coding [2], that is to say that each of the odor quality results from activation of a pattern of ORs. The existence of an intersection of these ORs patterns supports the hypothesis that molecules involved in a mixture that elicits an emergent odor, recognize a common set of ORs. References 1. Buck, Axel (1991) Cell, 65: 175-187 2. Malnic, Hirono, et al. (1999) Cell, 96: 713-723 3.Thomas-Danguin, Sinding, et al. (2014) Front Psychol, 5: 504 4. Coureaud, Hamdani, et al. (2009) J Exp Biol, 212: 2525-2531 5. Le Berre, Thomas-Danguin, et al. (2008) Chem Senses, 33: 193-199 6. Furudono, Sone, et al. (2009) Chem Senses, 34: 151-158 7. Saito, Chi, et al. (2009) Sci Signal, 2: 1-14 8. Clement, Mehl (2000) In: Pharmacophore perception (Güner, Ed.; Int. Univ. Line: La Jolla: p. 69-84)