Charting biologically relevant chemical space: A structural classification of natural products (SCONP)

The identification of small molecules that fall within the biologically relevant subfraction of vast chemical space is of utmost importance to chemical biology and medicinal chemistry research. The prerequirement of biological relevance to be met by such molecules is fulfilled by natural product-derived compound collections. We report a structural classification of natural products (SCONP) as organizing principle for charting the known chemical space explored by nature. SCONP arranges the scaffolds of the natural products in a tree-like fashion and provides a viable analysis- and hypothesis-generating tool for the design of natural product-derived compound collections. The validity of the approach is demonstrated in the development of a previously undescribed class of selective and potent inhibitors of 11 beta-hydroxy-steroid dehydrogenase type 1 with activity in cells guided by SCONP and protein structure similarity clustering. 11 beta-hydroxy-steroid dehydrogenase type 1 is a target in the development of new therapies for the treatment of diabetes, the metabolic syndrome, and obesity.