The relationship between molecular structure and odor has fascinated and puzzled chemists for more than a century. Despite a great deal of research on structure-odor relationships, prediction of the odor of a novel molecule remains a statistical exercise and models only provide a probability of the character, threshold, and intensity. Surprises are still commonplace, and serendipity continues to be an important factor in the discovery of novel fragrant molecules. Recent advances in our understanding of the mechanism of olfaction provide an explanation for this and suggest that our ability to predict odor properties of molecules will not improve significantly in the near future.

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Receptor-ligand interaction models are generally based on a 'lock and key' concept. How far this holds true for olfactory receptors and odor molecules is currently uncertain. Here, we have investigated the response of a human olfactory receptor, OR1D2, to a broad array of odorants and found that there is no simple, direct correlation between a molecule's ability to activate this receptor and the odor impression elicited in the brain. In a parallel study on specific anosmia, we have found no evidence for odor-specific anosmia to either musk or amber, but rather to specific molecules within these categories. Cluster analysis confirmed that there is no simple correlation between molecular structure and impaired perception in either odor type. There are some differences in patterns of impairment between the two odor types and some evidence to suggest that subjects with specific anosmia to a given substance can identify its presence in a mixture. Taken together, our results show that simplistic 'lock and key' models of olfaction based on a concept of odor-quality-tuned receptors are inadequate, irrespective of the nature of the lock-key interaction. Receptor activation is only one step in a long chain of events leading from inhalation of odorants to perception of odor in the higher brain, and, therefore, although structure-odor correlations are useful tools for the design of novel odorants, caution should be exercised when extrapolating them to models of olfactory perception. Those seeking to understand the odorant-receptor interaction should use receptor activation rather than odor as input data.

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In 1896, Tiemann first raised the question of whether or not enantiomers might exhibit different odors. The classic work of von Braun should have settled the issue in 1927 but the debate continued for decades, often rather acrimoniously. Various factors such as purity of samples and subjectivity of odors provided the confusion necessary to perpetuate disagreement. Nowadays, we have enough good-quality data to know that sometimes, absolute configuration affects odor perception and sometimes it does not. We are, therefore, left with some interesting academic and commercial questions to be addressed.