Structure Based Design and Synthesis of Novel Inhibitors of the Kinase IspE
Malaria is assumed to cause 300 to 500 million infections per year. Moreover, about one-third of the world population is infected with Mycobacterium tuberculosis. The emergence of multi-drug resistant strains of Plasmodium falciparum and Mycobacterium tuberculosis reveals the necessity of new drugs with novel modes of action. The non-mevalonate-pathway is used exclusively by many pathogens but not by humans for the biosynthesis of isoprenoids. This fact makes the enzymes of the non-mevalonate-pathways promising targets for the development of new drugs against Malaria and Tuberculosis.
The aim of this project is the de novo design and synthesis of inhibitors against 4-diphosphocytidyl-2C-methyl-D-erythritol kinase (CDP-ME kinase, IspE). The design will be done with MOLOC, a molecular modeling programm developed by Hoffmann-La Roche. Biological evaluation of the inhibitors and X-ray crystallography of protein-ligand complexes will be used to study and optimize promising inhibitors.