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

Abstract

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 11beta-hydroxysteroid dehydrogenase type 1 with activity in cells guided by SCONP and protein structure similarity clustering. 11beta-hydroxysteroid dehydrogenase type 1 is a target in the development of new therapies for the treatment of diabetes, the metabolic syndrome, and obesity.

Fig. 1.

Graphical star-like representation of the NP scaffold tree. For clarity of the graphic illustration, only scaffolds are shown that represent cumulatively at least 0.2% of the NP population in the DNP.

Fig. 2.

Strategic use of the NP tree. (A) The frequency distribution pattern first guided brachiation from the complex pentacyclic starting scaffold of GA (1) in the direction of reduced complexity to two- to four-ring-containing NPs, which are the most abundant ones (see Fig. 5). A second independent criterion (PSSC) finally leads to the selection of the 1,2,3,4,4a,5,6,7-octahydronaphthalene scaffold as biologically relevant starting point for compound library generation. (B) General structure of the library synthesized.

Fig. 3.

Inhibition of 11βHSD1-dependent translocation of GR by compound 5. HEK-293 cells were transfected with GFP-GR alone or together with 11βHSD1. Cells were incubated 6 h posttransfection in steroid-free medium for 18 h. Where indicated, cells were preincubated for 30 min with 25 μMGA, 3 or 10 μM of inhibitor 5, followed by incubation for another 40 min with 500 nM cortisone. GFP-GR was detected by immunofluorescence microscopy. By converting inactive cortisone to cortisol, 11βHSD1 mediated nuclear translocation of GR. Inhibition of 11βHSD1 prevented the formation of cortisol and nuclear translocation of GR.