When I look at potently bioactive molecules, I can’t help but think of a “David vs Goliath” biblical analogy. An why not, especially when something that is rather miniscule (a small molecule) exerts a profound effect on a molecular entity that is orders of magnitude larger (a protein)? I particularly appreciate subtle aspects of molecular interactions, especially if there is a stereoelectronic effect that is linked to a biological outcome. In the past, I commented on such findings several times and will continue to do so because this is perhaps the main reason why organic chemistry is second to none in terms of pure intellectual delight.
David Fairlie of the University of Queensland was one of the speakers at the American Peptide Symposium I organized with Ved Srivastava this past June. In his lecture, David showed the following two molecules. The one on the left agonizes the C3a receptor (a G-protein coupled receptor), whereas the one on the left antagonizes the C3a target. Given the diametrically opposite effects of activating vs deactivating the receptor, a question arises about the underlying causes. In their JACS article, the Fairlie team provides convincing evidence that the observed effect is due to the preferred population of two different rotamers about the amide carbonyl and the heterocycle. This is a great example of how stereoelectronic effects in heterocycles dictate different dipole relationships, which in turn modulates molecular conformation and leads to different biological properties.