Abstract

Most of the approaches used in the structure-based design of inhibitors of enzymes are based on docking or virtual screening studies using the available crystal structures in which the enzyme is considered a rigid mold. However, enzymes are “dynamic” systems that are able to adopt diverse conformations during catalysis and this could also be exploited in inhibitor design since the flexibility is essential for catalysis. It seems reasonable that for enzyme inhibitor design, in addition to stabilizing a closed disposition of the active site that prevents the entry of the substrate(s), disabling the closure of the active site for catalysis could also be an interesting alternative strategy. This motion-based approach allows the design of ligands that target additional cavities generated during this motion but have limited (or no) access in the closed conformation.

The possible development of new antibiotics by the selective and effective inhibition of shikimate kinase (SK), which is an essential enzyme in bacteria that does not have any counterpart in human cells, is presented. Competitive reversible inhibitors of the SK enzyme from M. tuberculosis and H. pylori that block the closure of the active site by reducing the flexibility of the LID and SB domains were identified showing to have good in vitro activity.