Structure-based discovery of a family of synthetic cyclophilin inhibitors showing a cyclosporin-A phenotype in Caenorhabditis elegans.

Abstract

Cyclophilins, which are found in all cellular compartments and with diverse biological roles, are now drug targets for a number of diseases including HIV infection, malaria and ischaemia. We used the database-mining program LIDAEUS and in silico screening to discover the dimedone family of inhibitors which show a conserved 'ball and socket' binding mode with a dimethyl group in the hydrophobic binding pocket of human cyclophilin A (CypA) mimicking a key interaction of the natural inhibitor cyclosporin A (CsA). The most potent derivative binds CypA with a K(d) of 11.2+/-9.2 microM and an IC50 for activity against Caenorhabditis elegans (C. elegans) of 190 microM compared to 28 microM for CsA. These dimedone analogues provide a new scaffold for the synthesis of families of peptidomimetic molecules with potential activity against HIV, malaria, and helminth parasite infections.

• Authors: Yuande Yang, Elizabeth Moir, George Kontopidis, Paul Taylor, Martin A Wear, Kirk Malone, Colin J Dunsmore, Antony P Page, Nicholas J Turner, Malcolm D Walkinshaw
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 363 Issue 4 Pg. 1013-9 (Nov 30 2007) ISSN: 1090-2104 [Electronic] United States
• PMID: 17927958 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclohexanones
• Enzyme Inhibitors
• Cyclosporine
• dimedone
• Cyclophilin A

Topics

• Animals
• Caenorhabditis elegans (drug effects, enzymology)
• Crystallography, X-Ray
• Cyclohexanones (chemical synthesis, chemistry, classification, pharmacology)
• Cyclophilin A (antagonists & inhibitors, chemistry, metabolism)
• Cyclosporine (chemistry, pharmacology)
• Enzyme Inhibitors (chemical synthesis, chemistry, classification, pharmacology)
• Humans
• Hydrophobic and Hydrophilic Interactions
• Models, Molecular
• Molecular Structure
• Phenotype
• Protein Binding
• Structure-Activity Relationship