title: 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.affiliation: The Centre for Translational and Chemical Biology, The University of Edinburgh, Michael Swann Building, King's Buildings, Edinburgh EH9 3JR, UK.
authors.forename: Yuande
authors.initials: Y
authors.lastname: Yang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Moir
authors.forename: George
authors.initials: G
authors.lastname: Kontopidis
authors.forename: Paul
authors.initials: P
authors.lastname: Taylor
authors.forename: Martin A
authors.initials: MA
authors.lastname: Wear
authors.forename: Kirk
authors.initials: K
authors.lastname: Malone
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Dunsmore
authors.forename: Antony P
authors.initials: AP
authors.lastname: Page
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Turner
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Walkinshaw
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000201:enzymology*; D018360:Crystallography, X-Ray; D003512:Cyclohexanones / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D021984:Cyclophilin A / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016572:Cyclosporine / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D010641:Phenotype; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D016572:Cyclosporine; C004774:dimedone; D021984:Cyclophilin A