| Structural highlights
Function
[PKNG_MYCTU] Phosphorylates GarA. May play a role in metabolic regulation via control of the phosphorylation status of GarA. Plays a crucial role in the survival of mycobacteria within host macrophages, by blocking the intracellular degradation of mycobacteria in lysosomes. Required for intrinsic antibiotic resistance.[1] [2] [3] [4]
Publication Abstract from PubMed
Computer-aided drug discovery methods play a major role in the development of therapeutically important small molecules, but their performance needs to be improved. Molecular dynamics simulations in mixed solvents are useful in understanding protein-ligand recognition and improving molecular docking predictions. In this work, we used ethanol as a cosolvent to find relevant interactions for ligands toward protein kinase G, an essential protein of Mycobacterium tuberculosis (Mtb). We validated the hot spots by screening a database of fragment-like compounds and another one of known kinase inhibitors. Next, we performed a pharmacophore-guided docking simulation and found three low micromolar inhibitors, including one with a novel chemical scaffold that we expanded to four derivative compounds. Binding affinities were characterized by intrinsic fluorescence quenching assays, isothermal titration calorimetry, and the analysis of melting curves. The predicted binding mode was confirmed by X-ray crystallography. Finally, the compounds significantly inhibited the viability of Mtb in infected THP-1 macrophages.
Cosolvent Sites-Based Discovery of Mycobacterium Tuberculosis Protein Kinase G Inhibitors.,Burastero O, Defelipe LA, Gola G, Tateosian NL, Lopez ED, Martinena CB, Arcon JP, Traian MD, Wetzler DE, Bento I, Barril X, Ramirez J, Marti MA, Garcia-Alai MM, Turjanski AG J Med Chem. 2022 Jun 23. doi: 10.1021/acs.jmedchem.1c02012. PMID:35737472[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ O'Hare HM, Duran R, Cervenansky C, Bellinzoni M, Wehenkel AM, Pritsch O, Obal G, Baumgartner J, Vialaret J, Johnsson K, Alzari PM. Regulation of glutamate metabolism by protein kinases in mycobacteria. Mol Microbiol. 2008 Dec;70(6):1408-23. doi: 10.1111/j.1365-2958.2008.06489.x., Epub 2008 Oct 17. PMID:19019160 doi:http://dx.doi.org/10.1111/j.1365-2958.2008.06489.x
- ↑ Wolff KA, Nguyen HT, Cartabuke RH, Singh A, Ogwang S, Nguyen L. Protein kinase G is required for intrinsic antibiotic resistance in mycobacteria. Antimicrob Agents Chemother. 2009 Aug;53(8):3515-9. doi: 10.1128/AAC.00012-09., Epub 2009 Jun 15. PMID:19528288 doi:http://dx.doi.org/10.1128/AAC.00012-09
- ↑ Tiwari D, Singh RK, Goswami K, Verma SK, Prakash B, Nandicoori VK. Key residues in Mycobacterium tuberculosis protein kinase G play a role in regulating kinase activity and survival in the host. J Biol Chem. 2009 Oct 2;284(40):27467-79. doi: 10.1074/jbc.M109.036095. Epub 2009, Jul 28. PMID:19638631 doi:http://dx.doi.org/10.1074/jbc.M109.036095
- ↑ Scherr N, Honnappa S, Kunz G, Mueller P, Jayachandran R, Winkler F, Pieters J, Steinmetz MO. Structural basis for the specific inhibition of protein kinase G, a virulence factor of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12151-6. Epub 2007 Jul 6. PMID:17616581
- ↑ Burastero O, Defelipe LA, Gola G, Tateosian NL, Lopez ED, Martinena CB, Arcon JP, Traian MD, Wetzler DE, Bento I, Barril X, Ramirez J, Marti MA, Garcia-Alai MM, Turjanski AG. Cosolvent Sites-Based Discovery of Mycobacterium Tuberculosis Protein Kinase G Inhibitors. J Med Chem. 2022 Jun 23. doi: 10.1021/acs.jmedchem.1c02012. PMID:35737472 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c02012
|
