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Scientists discover a new structural class of enzyme inhibitors

Max Planck Society : 12 November, 2006  (New Product)
Natural products have always been an important source for the development of chemical tool compounds or drugs respectively in chemical biology and pharmaceutical research. Researchers frequently build up what are known as 'combinatorial libraries' based on the structural characteristics of natural products.
Scientists from the Max Planck Institute of Molecular Physiology in Dortmund, Germany have now described the structural interrelationships between natural products by analyzing some 200,000 of them in co-operation with scientists from the pharmaceutical company Novartis in Basel, Switzerland. This analysis led to a new classification of natural products based on their structure, called SCONP (Structural Classification Of Natural Products). Guided by SCONP, the researchers developed a new structural class of inhibitors of 11b-hydroxysteroid dehydrogenase type 1. Inhibition of this enzyme is being discussed as a promising approach for the treatment of obesity, the metabolic syndrome, diabetes type 2, and cognitive dysfunction.

Scientists working with Professor Herbert Waldmann have been focusing their interest on biologically relevant starting points for the targeted development of drug-like molecules capable of influencing the function of disease-related proteins. Natural products are particularly well-suited to be such starting points. They are produced for very specific biological purposes by the respective organism. Natural products play a role in chemical defence and communication.

Natural products are synthesized by specific enzymes and, over the course of evolution, have been optimized for their particular function. The chemical structures of natural products are thus 'privileged' in the sense that they are part of the 'chemical space', used by nature for small organic molecules. One can imagine the totality of all thinkable chemical structures as an infinite space, not unlike our universe. In this picture, single chemical molecules represent 'stars' and groups of molecules 'galaxies'.

The researchers in Dortmund, in co-operation with Novartis, have investigated the scaffolds of natural products and then classified them hierarchically, by scaffold size and complexity, into a tree-like diagram. The scientists generated structure-based 'genealogies' of the natural product scaffolds and correlated them with each other. Each natural product scaffold was thus traced back to a one ring scaffold as a single unit.

This yielded a kind of phylogenetic tree. Its scaffolds are classified exclusively on the basis of structural similarities and the number of rings in the scaffold. Every node in the tree diagram represents a certain scaffold. From such a node several branches may lead to nodes representing more complex scaffolds. This scaffold-based structural classification of natural products was, at each node, annotated with the biological source organism, and the biological effect, as far as it was known. In this way the researchers have developed the first exclusively structure-based ordering principle for natural products ('Structural Classification Of Natural Products'). It can help us navigate the 'chemical space' of natural products.

The researchers used SCONP together with PSSC as a secondary criterion. It is a concept that groups proteins on the basis of structural similarity. This allowed the development of structurally simplified, but effective and highly selective, inhibitors of the enzyme 11bHSD. The starting point was the complex natural product and non-selective 11bHSD inhibitor, glycyrrhetinic acid.

The analysis proceeded as follows. The scaffold of glycyrrhetinic acid (1) was assigned to the appropriate node in the SCONP tree. 'Brachiation' within the SCONP tree toward the roots, that is, in the direction of simpler scaffolds, led to a group of two, three, and four ring scaffolds, which appear most frequently in nature. This finding is based on a statistical analysis of the frequency of occurrence of the natural product scaffolds. Out of this subset of natural product scaffolds, and using PSSC as a second, independent criterion, the researchers chose the octahydronaphthaline scaffold, which is also found in the natural product dysidiolide.

Based on this analysis they built up a collection of 162 compounds with octahydronaphthaline scaffold. They further investigated whether the compounds could inhibit the enzyme 11bHSD1. In total, 30 different inhibitors could be identified in the compound library. Four of them inhibited the enzyme in the nanomolar range. Cellular activity of this new structural class of 11bHSD1 inhibitors could be shown with the most active and selective compound.

The researchers now plan to refine their classification concept, and they hope to give more examples of how to use this concept for the development of new chemical tool compounds and drugs.
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