IspD (4-Diphosphocytidyl-2C-methyl-D-erythritol Synthase, EC 2.7.7.60) is an enzyme of the non-mevalonate pathway of isoprenoid biosynthesis. This pathway occurs in many bacteria, some algae, plants, and in certain protozoa such as the malaria parasite Plasmodium, but is absent in humans. Thus, these enzymes are highly interesting drug targets for antimalarials, antibiotics or herbicides. The rising emergence of multi-drug resistant pathogens and weeds underline the necessity of new drug development with novel mode of action.In a combined approach of high throughput screening and computer-assisted drug design, we published the first inhibitors for IspD [Angew. Chem. Int. Ed. 2011 , 50, 7931�7935]. We revealed an allosteric binding site in IspD from Arabidopsis thaliana and could proof the binding mode by co-crystal structure analysis (Figure below: PDB code 2YC5, 1.6 � resolution). Lead optimization by molecular modeling and distinct water replacement resulted in an improved IC50 value of 35 � 7 nM.

Lead discovery and optimization for IspD

244th National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.