NOVEL MYCOBACTERIUM TUBERCULOSIS PKNG INHIBITORS. A COMPUTATIONAL-EXPERIMENTAL STUDY

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

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Tuberculosis is a chronic disease caused by the bacillusMycobacterium tuberculosis (Mtb) that remains a leadingcause of mortality worldwide. The search for new protein tar-gets and their inhibitory compounds became a priority dueto the emergence of multidrug and extremely drug resistantstrains. Pkns are the main kinase family in Mtb, consistingof 11 members including pknG, a protein that plays a centralrole in energy metabolism and the infection process makingit an excellent target for drug design. In the present work,we have used docking and molecular dynamics simulationsto search for a competitive inhibitor of the ATP binding siteof pknG. Three different libraries of small compounds: 1) astandard purchasable compound library of 2.7 million com-pounds; 2) a kinase focused set from GSK consisting of 360compounds, and 3) a small fragment based library of 600compounds. The docking was performed with the rDock pro-gram using a pharmacophoric restraint on the kinase hingeinteractions. Docking top rank compounds were subject to aprotocol of dynamic undocking for further evaluation. Finally,the best 12 compounds from the first set, all the fragments,and the best 10 GSK compounds were tested for inhibitionof in vitro kinase activity. We only found actives in the frag-ment set, which will be further evolved into a full-size druglike compounds.