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 silica 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 mu M and an IC50 for activity against Caenorhabditis elegans (C elegans) of 190 mu M compared to 28 mu M 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. (C) 2007 Elsevier Inc. All rights reserved.