Applying medicinal chemistry strategies to understand odorant discrimination

Abstract

Associating an odorant's chemical structure with its percept is a long-standing challenge. One hindrance may come from the adoption of the organic chemistry scheme of molecular description and classification. Chemists classify molecules according to characteristics that are useful in synthesis or isolation, but which may be of little importance to a biological sensory system. Accordingly, we look to medicinal chemistry, which emphasizes biological function over chemical form, in an attempt to discern which among the many molecular features are most important for odour discrimination. Here we use medicinal chemistry concepts to assemble a panel of molecules to test how heteroaromatic ring substitution of the benzene ring will change the odour percept of acetophenone. This work allows us to describe an extensive rule in odorant detection by mammalian olfactory receptors. Whereas organic chemistry would have predicted the ring size and composition to be key features, our work reveals that the topological polar surface area is the key feature for the discrimination of these odorants.

Bioisosterism reveals new structure-odor relationships

“…There is also a significant overlap between the aliphatic and aromatic odorants, as well as non-aldehyde ACE greatly overlapping with the rest of the aldehydes. While many panels used in traditional literature on functional imaging of OSNs has categorized odorants based on their functional groups [3][4][5][6][7][8], our results suggest once again that functional groups should not be the primary distinguishing criteria for the odorants. CYC6-1 and CYC6-3, while sharing the chemical formula, TPSA, weight, and volume, show a surprisingly small amount of overlap, indicating a presence of a significant structural differentiator.…”

“…Such significant overlap between aldehydes and ketones, as well as ketones and esters, and on large scale screens, suggests strong link between odorants with different polar functional groups, and urges for further exploration of such link. Since our findings with heteroaromatic ketones suggest a TPSAbased trend in odorant-OR interaction [3], perhaps this variable could be a starting point for a large-scale probing of the relationship among the functional groups in structurally analogous compounds.…”

“…Since the discovery of the Odor Receptors ORs, the olfactory field has relied on the concept of a reciprocal combinatorial code, whereby each chemical odorant can be detected by different ORs and each OR can detect a group of different chemicals [10]. Devising odorant panels using such rational method has shown great success, demonstrating OR tuning preferences among cyclic ketones based on the topological polar surface area (TPSA) descriptor [3]. Among other findings, we also saw the fluidity by which ORs may recognize esters, flipped esters, and ketones with an overall similar topological structure, which runs contrary to the widely held practice of using functional group as the main identifier of the odor grouping [4].…”

“…In previous work we have looked at the roles of heteroatomic ring substitutions and esters which have a particularly malleable structure. In both cases we found that the biological responses could be grouped according to relatedness and these groupings differed from those that a chemical classification program produced [3,4]. In this paper we further examine the role of bioisostereism by focusing on non-classical bioisosterism, which introduces seemingly structurally discrepant groups as biological substituents.…”

“…A critical finding by Manic et al[10] indicates that each mature OSN only expresses one type of OR, allowing for high throughput screening of carefully crafted odorant panels using dissociated OSN calcium imaging. Using this feature of the olfactory system, our previous work has probed how widely utilized bioisosteres in medicinal chemistry field relate to each other in terms of OR activation[3,4,6,11].…”