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 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.

[1]  Ray A. Jarvis,et al.  Clustering Using a Similarity Measure Based on Shared Near Neighbors , 1973, IEEE Transactions on Computers.

[2]  David Weininger,et al.  SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules , 1988, J. Chem. Inf. Comput. Sci..

[3]  M. Kelly-Borges,et al.  Dysidiolide: A Novel Protein Phosphatase Inhibitor from the Caribbean Sponge Dysidea etheria de Laubenfels , 1996 .

[4]  Yvonne C. Martin,et al.  Use of Structure-Activity Data To Compare Structure-Based Clustering Methods and Descriptors for Use in Compound Selection , 1996, J. Chem. Inf. Comput. Sci..

[5]  I. Macara,et al.  Evidence using a green fluorescent protein-glucocorticoid receptor chimera that the Ran/TC4 GTPase mediates an essential function independent of nuclear protein import , 1996, The Journal of cell biology.

[6]  G. Bemis,et al.  The properties of known drugs. 1. Molecular frameworks. , 1996, Journal of medicinal chemistry.

[7]  A. Odermatt,et al.  The N-terminal Anchor Sequences of 11β-Hydroxysteroid Dehydrogenases Determine Their Orientation in the Endoplasmic Reticulum Membrane* , 1999, The Journal of Biological Chemistry.

[8]  Thomas Henkel,et al.  Statistical Investigation into the Structural Complementarity of Natural Products and Synthetic Compounds. , 1999, Angewandte Chemie.

[9]  Ajay,et al.  The SHAPES strategy: an NMR-based approach for lead generation in drug discovery. , 1999, Chemistry & biology.

[10]  Hans Matter,et al.  Comparing 3D Pharmacophore Triplets and 2D Fingerprints for Selecting Diverse Compound Subsets , 1999, J. Chem. Inf. Comput. Sci..

[11]  J. Casida,et al.  Combinatorial synthesis of novel and potent inhibitors of NADH:ubiquinone oxidoreductase. , 2000, Chemistry & biology.

[12]  V. Křen,et al.  Glycosides in medicine: "The role of glycosidic residue in biological activity". , 2001, Current medicinal chemistry.

[13]  G. Schneider,et al.  Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries. , 2001, Journal of combinatorial chemistry.

[14]  A. Odermatt,et al.  The Intracellular Localization of the Mineralocorticoid Receptor Is Regulated by 11β-Hydroxysteroid Dehydrogenase Type 2* , 2001, The Journal of Biological Chemistry.

[15]  Robert P Sheridan,et al.  Why do we need so many chemical similarity search methods? , 2002, Drug discovery today.

[16]  Herbert Waldmann,et al.  From protein domains to drug candidates-natural products as guiding principles in the design and synthesis of compound libraries. , 2002, Angewandte Chemie.

[17]  G. Klebe,et al.  A new method to detect related function among proteins independent of sequence and fold homology. , 2002, Journal of molecular biology.

[18]  A. Odermatt,et al.  A rapid screening assay for inhibitors of 11β-hydroxysteroid dehydrogenases (11β-HSD): flavanone selectively inhibits 11β-HSD1 reductase activity , 2003, Molecular and Cellular Endocrinology.

[19]  Miklos Feher,et al.  Property Distributions: Differences between Drugs, Natural Products, and Molecules from Combinatorial Chemistry , 2003, J. Chem. Inf. Comput. Sci..

[20]  B. Shoichet,et al.  A specific mechanism of nonspecific inhibition. , 2003, Journal of medicinal chemistry.

[21]  Herbert Waldmann,et al.  Protein Structure Similarity as Guiding Principle for Combinatorial Library Design , 2003, Biological chemistry.

[22]  C. Dobson Chemical space and biology , 2004, Nature.

[23]  H. Waldmann,et al.  Synthesis and biological evaluation of an indomethacin library reveals a new class of angiogenesis-related kinase inhibitors. , 2004, Angewandte Chemie.

[24]  J. Gershenzon,et al.  Successful herbivore attack due to metabolic diversion of a plant chemical defense. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Herbert Waldmann,et al.  Compound library development guided by protein structure similarity clustering and natural product structure. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Hugo Kubinyi,et al.  Chemogenomics in Drug Discovery: A Medicinal Chemistry Perspective , 2004 .

[27]  Peter Willett,et al.  Enhancing the Effectiveness of Virtual Screening by Fusing Nearest Neighbor Lists: A Comparison of Similarity Coefficients , 2004, J. Chem. Inf. Model..

[28]  P. Schultz,et al.  Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway. , 2004, Chemistry & biology.

[29]  Christopher T. Walsh,et al.  Lessons from natural molecules , 2004, Nature.

[30]  I. E. Woodrow,et al.  Mini-Review: Constraints on Effectiveness of Cyanogenic Glycosides in Herbivore Defense , 2002, Journal of Chemical Ecology.

[31]  Ian J. Deary,et al.  11β-Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics , 2004 .

[32]  H. Waldmann,et al.  Modulation of MRP-1-mediated multidrug resistance by indomethacin analogues. , 2005, Journal of medicinal chemistry.

[33]  Ludger A. Wessjohann,et al.  What can a chemist learn from nature’s macrocycles? – A brief, conceptual view , 2005, Molecular Diversity.

[34]  Herbert Waldmann,et al.  Protein structure similarity clustering and natural product structure as guiding principles in drug discovery. , 2005, Drug discovery today.