Identification of Novel Inhibitors of Mycobacterium tuberculosis PknG using Pharmacophore based Virtual Screening, Docking, Molecular Dynamics Simulation and their Biological Evaluation

Abstract

PknG is a Ser/thr protein kinase that plays crucial role in regulatory processes within mycobacterial cell and signalling cascade of infected host cell. Essentiality of PknG in mycobacterial virulence by blocking phagosome-lysosome fusion as well as its role in intrinsic antibiotic resistance makes it an attractive drug target.However, only a very few compounds have been reported asMycobacteriumtuberculosis PknG(MtPknG) inhibitors so far.Therefore, in quest of finding potential inhibitors against MtPknG, we report here a sequential pharmacophore-based virtual screening workflow, three fold docking with different search algorithms and molecular dynamic simulations for better insight into predicted binding mode of identified hits.After detailed analysis of the results, six ligands were selected for in vitro analysis. Three of these molecules showed significant inhibitory activity against MtPknG. In addition,inhibitory studies of mycobacterial growth in infected THP-1 macrophages demonstrated considerable growth inhibition of M. bovis BCG induced through compound NRB04248 without any cytotoxic effect against host macrophages.Our results suggest that the compound NRB04248 can be exploredfor further design and optimization of MtPknG inhibitors.