Yang, Y., Moir, E., Kontopidis, G., Taylor, P., Wear, M. A., Malone, K., Dunsmore, C. J., Page, A. P., Turner, N. J. and Walkinshaw, M. D. (2007) Structure-based discovery of a family of synthetic cyclophilin inhibitors showing a cyclosporin-A phenotype in Caenorhabditis elegans. Biochemical and Biophysical Research Communications, 363(4), pp. 1013-1019. (doi: 10.1016/j.bbrc.2007.09.079) (PMID:17927958)
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Publisher's URL: http://dx.doi.org/10.1016/j.bbrc.2007.09.079
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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Page, Professor Tony and Walkinshaw, Mr Malcolm |
| Authors: | Yang, Y., Moir, E., Kontopidis, G., Taylor, P., Wear, M. A., Malone, K., Dunsmore, C. J., Page, A. P., Turner, N. J., and Walkinshaw, M. D. |
| Subjects: | Q Science > QH Natural history > QH345 Biochemistry |
| College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Biochemical and Biophysical Research Communications |
| Publisher: | Elsevier |
| ISSN: | 0006-291X |
| ISSN (Online): | 1090-2104 |
| Published Online: | 01 October 2007 |
| Related URLs: |
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