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

Biochem Biophys Res Commun. 2007 Nov 30;363(4):1013-9. doi: 10.1016/j.bbrc.2007.09.079. Epub 2007 Oct 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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