Figure 1.

Applied workflow that led to the discovery of new PknG inhibitors. First, ligand-binding hot spots were detected using MD in a mixture of ethanol and water. Second, hot spots were confirmed from two small screenings and used to design a scaffold and perform a tethered (structure-based) docking. Third, based on one of the hits, four derivatives were obtained, binding affinities were determined, and one inhibitor-bound crystal structure was solved. Lastly, inhibition of the survival of Mtb inside the macrophages was demonstrated.