Is It Possible to Predict the Odor of a Molecule on the Basis of its Structure?

Abstract

The olfactory sense is the dominant sensory perception for many animals. When Richard Axel and Linda B. Buck received the Nobel Prize in 2004 for discovering the G protein-coupled receptors' role in olfactory cells, they highlighted the importance of olfaction to the scientific community. Several theories have tried to explain how cells are able to distinguish such a wide variety of odorant molecules in a complex context in which enantiomers can result in completely different perceptions and structurally different molecules. Moreover, sex, age, cultural origin, and individual differences contribute to odor perception variations that complicate the picture. In this article, recent advances in olfaction theory are presented, and future trends in human olfaction such as structure-based odor prediction and artificial sniffing are discussed at the frontiers of chemistry, physiology, neurobiology, and machine learning.

Keywords: flavor; odor; odorant; olfaction; olfactory sense; sensory perception; structure-function relationship; volatile organic compounds.

Figure 1

Examples of odorants with common functional groups and similar odors [23].

Figure 2

Examples of odorants with common functional groups and dissimilar odors [24].

Figure 3

Examples of enantiomeric compounds with dissimilar odors [31,33].

Figure 4

Examples of odorants with different structures and similar odors (musk) [32,37].

Figure 5

Example of the changing odorant character of a compound with slight structural modification.

Figure 6

Mechanisms of human olfaction. 1. Orthonasal olfaction; 2. retronasal olfaction; 3. nasal cavity; 4. olfactory bulb; A. mitral cell; B. glomerulus; C. axon; D. cilia; E. olfactory receptor; F. olfactory receptor neuron.

Figure 7

Cascade of reactions occurring when an odorant molecule enters the nasal cavity. Odorants cross the mucus directly or via transport proteins (Tp) and then reach the odor receptor, which undergoes structural modifications and activates G proteins (G). An active subunit (Ga) is liberated, activating the lyase adenylate cyclase, resulting in the conversion of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). The cAMP is able to open cyclic nucleotide-gated ion channels, allowing Ca²⁺ and Na⁺ ions to enter the cell, which results in the depolarization of the odor receptor neuron (ORN) and transmission of the information to the brain.

Figure 8

Olfactory receptor (OR) responses to odorants. Humans have approximatively 396 olfactory receptors (OR 1, OR 2, OR 3, etc.). A single olfactory receptor is able to recognize different odorant molecules. As an example, OR 1 is able to recognize molecules A, B, and C (d). The identification of a particular odorant is caused by the activation of a group of receptors with a special pattern (a, b, and c). For example, odorant A is recognized by OR 1 and OR 2 as a banana flavor (a). Molecule B is, in turn, recognized by OR 1 and OR 3 and identified as an orange flavor (b). Also, two distinct molecules can be recognized by the same receptors and identified as having the same odor (a and c). Indeed, odorant C is also recognized by OR 1 and OR 2 as a banana flavor (c).