ABSTRACT
Abdominal radiographs of a dog presented for anorexia and vomiting revealed an ill-defined increase in opacity caudal to the stomach and caudal displacement of the small intestines. Ultrasonographs revealed an enlarged liver lobe with vascular thrombosis. Left medial liver lobe torsion was confirmed at postmortem.
Subject(s)
Dog Diseases/diagnostic imaging , Liver Diseases/veterinary , Liver/diagnostic imaging , Animals , Dogs , Fatal Outcome , Female , Liver/pathology , Liver Diseases/diagnostic imaging , Torsion Abnormality/veterinary , UltrasonographyABSTRACT
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.
Subject(s)
Biological Products/chemistry , Biological Products/classification , Chemistry/methods , Databases, Factual , Informatics/methods , Software , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , Drug Design , Protein ConformationSubject(s)
Bacterial Proteins/antagonists & inhibitors , Depsipeptides/chemical synthesis , Depsipeptides/pharmacology , Enzyme Inhibitors/chemical synthesis , Mycobacterium tuberculosis/enzymology , Protein Tyrosine Phosphatases/antagonists & inhibitors , Recombinant Fusion Proteins/antagonists & inhibitors , Bacterial Proteins/metabolism , Depsipeptides/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Molecular Structure , Mycobacterium tuberculosis/drug effects , Peptide Library , Protein Tyrosine Phosphatases/metabolism , Pyrroles/pharmacology , Recombinant Fusion Proteins/metabolismABSTRACT
Natural products are biologically validated starting points for the design of combinatorial libraries, as they have a proven record of biological relevance. This special role of natural products in medicinal chemistry and chemical biology can be interpreted in the light of new insights about the domain architecture of proteins gained by structural biology and bioinformatics. In order to fulfil the specific requirements of the individual binding pocket within a domain family it is necessary to optimise the natural product structure by chemical variation. Solid-phase chemistry is becoming an efficient tool for this optimisation process, and recent advances in this field are highlighted in this review article.