Synthesis and Computational Analysis of Novel IspF Inhibitors

We present a mixed chemical, biological, and physical approach to the identification of novel inhibitors of 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (IspF). This enzyme is involved in the synthesis of an essential class of biomolecule in pathogens, isoprenoids. Therefore, a potent inhibitor of this enzyme has potential to produce a new class of antibiotics. A selection of potential inhibitors was generated using chemical methods and tested for activity against IspF using biological methods. These results were used to inform and verify the validity of a computational approach for identification of further inhibitors. This computational approach used Newtonian mechanics, the AMBER force field, and free energy perturbation to predict the relative inhibition of potential inhibitors.