Cosolvent Sites-Based Discovery of Mycobacterium Tuberculosis Protein Kinase G Inhibitors

Computer-aided
drug discovery methods play a major role in the
development of therapeutically important small molecules, but their
performance needs to be improved. Molecular dynamics simulations in
mixed solvents are useful in understanding protein–ligand recognition
and improving molecular docking predictions. In this work, we used
ethanol as a cosolvent to find relevant interactions for ligands toward
protein kinase G, an essential protein of Mycobacterium
tuberculosis (Mtb).
We validated the hot spots by screening a database of fragment-like
compounds and another one of known kinase inhibitors. Next, we performed
a pharmacophore-guided docking simulation and found three low micromolar
inhibitors, including one with a novel chemical scaffold that we expanded
to four derivative compounds. Binding affinities were characterized
by intrinsic fluorescence quenching assays, isothermal titration calorimetry,
and the analysis of melting curves. The predicted binding mode was
confirmed by X-ray crystallography. Finally, the compounds significantly
inhibited the viability of Mtb in infected
THP-1 macrophages.