CONICET | Buscador de Institutos y Recursos Humanos

Background: Tuberculosis is a chronic disease caused by the bacillus Mycobacterium tuberculosis (Mtb) that remains a leading cause of mortality worldwide. The search for new protein targets and their inhibitory compounds became a priority due to the emergence of multidrug and extremely drug-resistant strains. Pkns are the main kinase family in Mtb, consisting of 11 members including pknG, a protein that plays a central role in energy metabolism and the infection process making it an excellent target for drug design.Methods & Materials: In the present work, we have used docking and molecular dynamics simulations to search for a competitive inhibitor of the ATP binding site of pknG. Three different libraries of small compounds: 1) a standard purchasable compound library of 2.7 million compounds; 2) a kinase focused set from GSK consisting of 360 compounds, and 3) a small fragment-based library of 600 compounds. The docking was performed with the rDock program using a pharmacophoric restraint on the kinase hinge interactions. Docking top rank compounds were subject to a protocol of dynamic undocking for further evaluation. Finally, the best 12 compounds from the first set, all the fragments, and the best 23 GSK compounds were tested for inhibition of in vitro kinase activity.Results: Until now we found actives in the fragment, including one fragment with IC50 near 100 μM; which is promising due to the small size of the compound. GSK set reported one compound with IC50 near 40 μM.Conclusion: The fragment-based library was the one with the higher number of actives. We look forward to using the GSK compound core for further development of new inhibitors and also to further evolve the hit fragments into full-size drug-like compounds.