Novel Mycobacterium tuberculosis PknG inhibitors. A computational-experimental study

BURASTERO, OSVALDO; LOPEZ, ELIAS D.; TURJANSKI, ADRIÁN G.; DEFELIPE, LUCAS A.; ARCON, JUAN PABLO; BARRIL, XAVIER; MARTI, MARCELO A.

Buenos Aires

Congreso; ICID 2018; 2018

ISID

Background: Tuberculosis is a chronic disease caused by the bacillus Mycobacterium tuberculosis (Mtb)that remains a leading cause of mortality worldwide. The search fornew protein targets and their inhibitorycompounds 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 acentral 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 tosearch for a competitive inhibitor of the ATP binding site of pknG. Three different libraries of smallcompounds: 1) a standard purchasable compound library of 2.7 million compounds; 2) a kinasefocusedset from GSK consisting of 360 compounds, and 3) a small fragment based library of 600 compounds.The docking was performed with the rDockprogram using a pharmacophoric restraint on the kinase hingeinteractions. Docking top rank compounds were subject to a protocol of dynamic undocking for furtherevaluation. Finally, the best 12 compounds from the first set, all the fragments, and the best 23 GSKcompounds 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 uM;which is promising due to the small size of the compound. GSK set reported one compound with IC50near 40 uM.Conclusion: The fragment based library was the one with the higher number of actives. We look forwardto use the GSK compound core to future development of new inhibitors and also to further evolve the hitfragments into full-size drug like compounds.