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Functional odor classification through a medicinal chemistry approach

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Science Advances  09 Feb 2018:
Vol. 4, no. 2, eaao6086
DOI: 10.1126/sciadv.aao6086
  • Fig. 1 Ester group manipulations.

    These structures show the relations between the odorants of our panel. All the odorants of this panel have a nine-atom-long backbone chain. (A) [1] and [2] are terminal reverse esters. Their ether oxygen and the carbonyl are reciprocally transposed so that the carbonyl is now situated where the ether oxygen used to be. They both have one six-carbon nonpolar “arm” and a terminal polar group. (B) [5] and [6] are medial reverse esters. Their ether oxygen and the carbonyl are reciprocally transposed. They both have two nonpolar carbon chain “arms” and a central polar group. (C) [3] represents a two-carbon terminal-to-medial shift of the ester group compared to [1]. (D) The ketone [4] represents an O→C substitution compared to both [5] and [3]. (E) [3] and [1] have their ether oxygen located at the same relative position of their backbone chain but represent a symmetrical displacement of the carbonyl around this ether oxygen. (F) [5] and [3] have their carbonyl located at the same relative position along their backbone chain but represent a symmetrical displacement of their ether oxygen around this carbonyl.

  • Fig. 2 Responses of dissociated OSNs to ester odorants.

    (A) A total of 872 of 4523 viable OSNs responded to at least one odorant, leading to 58 distinct binary response patterns (enumerated on the left). The numbers in the rightmost column indicate how often a particular response pattern was observed. A green box denotes activation of the OSN by the corresponding odorant. (B) Two-dimensional (2D) representations of the tested odorants. (C) Coactivation of OSNs responding to each of the five esters plotted according to ester group displacement along the carbon chain of the primary odorant (numbers above each graph). Reverse esters, denoted by the purple bar, revealed the highest levels of coactivation for both medial and terminal esters, although the terminal esters represent a four-carbon displacement. Pairwise coactivation values are provided in fig. S1. Examples of OSNs’ Ca2+ response traces are provided in fig. S4.

  • Fig. 3 Hierarchical clustering analysis of tested esters.

    (A) Odorants clustered according to chemical similarity as evaluated by 1666 molecular descriptors downloaded through the e-Dragon applet. Note that in this chemical-based clustering, the major division is the functional group (that is, ester or ketone). C denotes the cophenetic correlation coefficient. (B) Odorants clustered according to biological response similarity based on calcium imaging of dissociated OSNs (form the data shown in Fig. 2). In this biology-centric classification, the relative positions of the functional group (that is, medial or terminal) emerge as the main organizational feature of the classification. The closest odorants appear to be reverse esters in both medial and terminal clusters. All distances in the dendrograms are Euclidean. See Materials and Methods for the details of dendrogram generation. The top 20 e-Dragon descriptors that best recapitulate the OSN responses to the esters ([1], [2], [3], [5], and [6]) are provided in table S1.

  • Fig. 4 Habituation-dishabituation olfactory test.

    Histograms indicate the average olfactory investigation time (in seconds) by mice during repetitive 2-min exposures to odorant pairs or dimethyl sulfoxide (DMSO) (solvent). Mice that habituated to the terminal ester [1] remained habituated to its reverse ester [2] (A) but dishabituated to the medial ester [5] (B) and the ketone [4] (C). Similarly, mice that habituated to the medial ester [5] remained habituated to its reverse ester [6] (D) but dishabituated to the medial ester [3] (E) and the ketone [4] (F). Note that these behaviors recapitulate the ester classification obtained from the dissociated OSN response in Fig. 3. Behavioral data were analyzed using the analysis of variance (ANOVA) test, followed by a post hoc paired t test (*P < 0.05 and **P < 0.005, paired post hoc t test). n.s., not significant. Error bars indicate SEM. Between 9 and 12 animals were tested for each pair of esters.

  • Fig. 5 Human olfactory discrimination tests.

    (A) 3D representations of the tested odorants. (B) Odorants clustered according to similarity based on 11 human subjects’ perception of 30 μM odorant solutions over three iterations. All distances in the dendrograms are Euclidean. See Materials and Methods for the details of dendrogram generation. The two reverse medial esters [5] and [6] were grouped together more frequently than the two odorant solutions containing [1] (iteration results are reported in fig. S3). (C) Histograms represent the percentage of correct identification by human subjects of the different 3 mM odorant solution [x] [that is, [2], [3], [5] or blank (Blk)] from the two identical 3 mM odorant solutions containing [1]; chance level (33%) is shown by the red dashed line. n = 13 volunteers. (D) Histograms represent the percentage of correct identification made by the human subjects of the different 3 mM odorant solution [x] (that is, [2], [3], [5] or blank) from the two identical 3 mM odorant solutions containing [1]; chance level (33%) is shown by the red dashed line. n = 14 subjects.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/4/2/eaao6086/DC1

    fig. S1. OSN coactivation table.

    fig. S2. Venn diagram representation of the overlapping activation of OSNs by esters.

    fig. S3. Human olfactory discrimination test repetitions.

    fig. S4. Examples of OSNs’ Ca2+ responses to the odorant panel.

    table S1. Top 20 e-Dragon descriptors describing distances between the esters.

  • Supplementary Materials

    This PDF file includes:

    • fig. S1. OSN coactivation table.
    • fig. S2. Venn diagram representation of the overlapping activation of OSNs by esters.
    • fig. S3. Human olfactory discrimination test repetitions.
    • fig. S4. Examples of OSNs’ Ca2+ responses to the odorant panel.
    • table S1. Top 20 e-Dragon descriptors describing distances between the esters.

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