title: 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 a crucial role in regulatory processes within the mycobacterial cell and signaling cascade of the infected host cell. The 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 very few compounds have been reported as Mycobacterium tuberculosis PknG (MtPknG) inhibitors so far. Therefore, in an effort to find potential inhibitors against MtPknG, we report here a sequential pharmacophore-based virtual screening workflow, 3-fold docking with different search algorithms, and molecular dynamic simulations for better insight into the 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 explored for further design and optimization of MtPknG inhibitors.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Singh
authors.forename: Sameer
authors.initials: S
authors.lastname: Tiwari
authors.affiliation: §Academy of Scientific and Innovative Research, New Delhi 110025, India.
authors.forename: Kishore K
authors.initials: KK
authors.lastname: Srivastava
authors.affiliation: §Academy of Scientific and Innovative Research, New Delhi 110025, India.
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Siddiqi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008264:Macrophages / Q000382:microbiology; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000502:physiology; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014584:User-Computer Interface
chemical_list: D001426:Bacterial Proteins; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; C000605609:protein kinase G, Mycobacterium tuberculosis