Combinatorial chemical synthesis can rapidly generate many different compounds, but they often share an underlying structure that represents a fairly small region of chemical space. Lam et al. used a dynamic combinatorial approach to discover a surprisingly elaborate structure for binding the acetylcholine neurotransmitter. The authors added synthetic dipeptides to an acetylcholine solution under conditions allowing reversible coupling. At equilibrium, the predominant structure that had self-assembled as a receptor was a pair of linked 42-membered rings, each a trimer of the dipeptide building blocks. This catenane molecule was isolated in 65% yield and showed a 100 nanomolar affinity for the neurotransmitter.
R. T. S. Lam, A. Belenguer, S. L. Roberts, C. Naumann, T. Jarrosson, S. Otto, J. K. M. Sanders, Amplification of acetylcholine-binding catenanes from dynamic combinatorial libraries. Science 308, 667-669 (2005). [Abstract] [Full Text]