First X-ray Cocrystal Structure of a Bacterial FabH Condensing Enzyme and a Small Molecule Inhibitor Achieved Using Rational Design and Homology Modeling

Abstract

The first cocrystal structure of a bacterial FabH condensing enzyme and a small molecule inhibitor is reported. The inhibitor was obtained by rational modification of a high throughput screening lead with the aid of a S. pneumoniae FabH homology model. This homology model was used to design analogues that would have both high affinity for the enzyme and appropriate aqueous solubility to facilitate cocrystallization studies.