A study of ring size patterns on the natural selection of macrocycles is presented. Chemical literature provided structural information for the study. Analysis of 4000 natural products reveal that about one in five possess a macrocycle structure, where an unexpected preference exists for 14-, 16-, and 18-membered ring systems. An even-over-odd preference exists in natural product macrocycles from terrestrial and marine sources. Natural 14-, 16-, and 18-membered rings predominate in heterocycle, carbocycle, and cyclic peptide structures, implying an origin independent of a two carbon (acetate) bioinsertion pathway. The origin of the preference would be difficult to examine biochemically because of the large number of individual biosynthetic pathways. However, the results raise an interesting question concerning the limited diversity of macrocycle ring sizes and the nature of the constraints that may cause them. Implications for drug design will be discussed.
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