Title:

Charting Biologically Relevant Chemical Space: 
A Structural Classification of Natural Products (SCONP)

Author:

Wetzel, S., Dortmund/D, Ertl, P., Basel/CH, Schuffenhauer, A.,
Basel/CH, Waldmann, H., Dormund/D

Prof. Dr. Herbert Waldmann, Max-Planck-Institute for Molecular Physiology,
Otto-Hahn-Straße 11, 44227 Dortmund and University of Dortmund


Abstract:

Combinatorial chemistry and high throughput screening evolved as powerful tools in
drug discovery. But initial expectations that large libraries would yield more hits
and leads were not fulfilled and it has been realized that the biological relevance,
design, and diversity of the library are more important. Thus libraries based on
biologically relevant structures, e.g. natural products, can be expected to yield more
and possibly better modulators than others.[1] This immediately raises a key question:
where to find biologically validated starting points for library design in chemical
structure space?

"Space", as Douglas Adams famously said "is big. You just won't believe how
vastly, hugely, mind-bogglingly big it is."[2] Unknowingly, he thus prophesied one
of the great obstacles in charting chemical space. Although natural product space is
just a comparably small subset of chemical structure space, it is highly diverse not
only in structure but also in biological activity. Therefore, initial reduction of the
structural diversity is a key step for any attempt to map natural product space. 

In our work we developed an abstracting chemoinformatic approach to chart natural
product space. Since chemical structures are part of the international chemical
language, we decided to do a structure based classification. As shown in the figure
below, we first extracted the scaffolds from the natural products and then arranged
these in a tree-like fashion according to substructure relationships.[3] 

[1]	R. Breinbauer, I. R. Vetter, H. Waldmann, Angew. Chem. 2002, 114, 3002-3015;
Angew. Chem. Int. Ed. 2002, 41, 2878-2890.
[2]	D. Adams, Hitchikers Guide to the Galaxy, Del Rey, Reissue Edition 1995.
[3]	M. A. Koch, A. Schuffenhauer, M. Scheck, S. Wetzel, M. Casaulta, A. Odermatt,
P. Ertl, and H. Waldmann, PNAS 2005, 102, 17272-17277.