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Discovery of mycobacterium tuberculosis InhA inhibitors by binding sites comparison and ligands prediction

(2016) JOURNAL OF MEDICINAL CHEMISTRY. 59(24). p.11069-11078
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Organization
Abstract
Drug discovery is usually focused on a single protein target; in this process, existing compounds that bind to related proteins are often ignored. We describe ProBiS plugin, extension of our earlier ProBiSi-ligands approach, which for a given protein structure allows prediction of its binding:sites and, for each binding site, the ligands from similar binding sites in the Protein Data Bank. We developed a new database of precalculated binding site comparisons of about 290000 proteins to allow fast prediction of binding sites in existing proteins. The plugin enables advanced viewing of predicted binding sites, ligands' poses, and their interactions in three-dimensional graphics. Using the InhA query protein, an enoyl reductase enzyme in the Mycobacterium tuberculosis fatty acid biosynthesis pathway, we predicted its possible ligands and assessed their inhibitory activity experimentally. This resulted in three previously unrecognized inhibitors with novel scaffolds, demonstrating the plugin's utility in the early drug discovery process.
Keywords
REDUCTASE FABI INHIBITORS, CARRIER PROTEIN REDUCTASE, ENOYL-ACP REDUCTASE, ANTIMYCOBACTERIAL ACTIVITY, MOLECULAR DOCKING, COUPLED RECEPTOR, DRUG DISCOVERY, TARGETING INHA, DATA-BANK, DESIGN

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Citation

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MLA
Štular, Tanja, et al. “Discovery of Mycobacterium Tuberculosis InhA Inhibitors by Binding Sites Comparison and Ligands Prediction.” JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, no. 24, 2016, pp. 11069–78.
APA
Štular, T., Lešnik, S., Rožman, K., Schink, J., Zdouc, M., Ghysels, A., … Konc, J. (2016). Discovery of mycobacterium tuberculosis InhA inhibitors by binding sites comparison and ligands prediction. JOURNAL OF MEDICINAL CHEMISTRY, 59(24), 11069–11078.
Chicago author-date
Štular, Tanja, Samo Lešnik, Kaja Rožman, Julia Schink, Mitja Zdouc, An Ghysels, Feng Liu, et al. 2016. “Discovery of Mycobacterium Tuberculosis InhA Inhibitors by Binding Sites Comparison and Ligands Prediction.” JOURNAL OF MEDICINAL CHEMISTRY 59 (24): 11069–78.
Chicago author-date (all authors)
Štular, Tanja, Samo Lešnik, Kaja Rožman, Julia Schink, Mitja Zdouc, An Ghysels, Feng Liu, Courtney C Aldrich, V Joachim Haupt, Sebastian Salentin, Simone Daminelli, Michael Schroeder, Thierry Langer, Stanislav Gobec, Dušanka Janežič, and Janez Konc. 2016. “Discovery of Mycobacterium Tuberculosis InhA Inhibitors by Binding Sites Comparison and Ligands Prediction.” JOURNAL OF MEDICINAL CHEMISTRY 59 (24): 11069–11078.
Vancouver
1.
Štular T, Lešnik S, Rožman K, Schink J, Zdouc M, Ghysels A, et al. Discovery of mycobacterium tuberculosis InhA inhibitors by binding sites comparison and ligands prediction. JOURNAL OF MEDICINAL CHEMISTRY. 2016;59(24):11069–78.
IEEE
[1]
T. Štular et al., “Discovery of mycobacterium tuberculosis InhA inhibitors by binding sites comparison and ligands prediction,” JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, no. 24, pp. 11069–11078, 2016.
@article{8501667,
  abstract     = {Drug discovery is usually focused on a single protein target; in this process, existing compounds that bind to related proteins are often ignored. We describe ProBiS plugin, extension of our earlier ProBiSi-ligands approach, which for a given protein structure allows prediction of its binding:sites and, for each binding site, the ligands from similar binding sites in the Protein Data Bank. We developed a new database of precalculated binding site comparisons of about 290000 proteins to allow fast prediction of binding sites in existing proteins. The plugin enables advanced viewing of predicted binding sites, ligands' poses, and their interactions in three-dimensional graphics. Using the InhA query protein, an enoyl reductase enzyme in the Mycobacterium tuberculosis fatty acid biosynthesis pathway, we predicted its possible ligands and assessed their inhibitory activity experimentally. This resulted in three previously unrecognized inhibitors with novel scaffolds, demonstrating the plugin's utility in the early drug discovery process.},
  author       = {Štular, Tanja and Lešnik, Samo and Rožman, Kaja and Schink, Julia and Zdouc, Mitja and Ghysels, An and Liu, Feng and Aldrich, Courtney C and Haupt, V Joachim and Salentin, Sebastian and Daminelli, Simone and Schroeder, Michael and Langer, Thierry and Gobec, Stanislav and Janežič, Dušanka and Konc, Janez},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  keywords     = {REDUCTASE FABI INHIBITORS,CARRIER PROTEIN REDUCTASE,ENOYL-ACP REDUCTASE,ANTIMYCOBACTERIAL ACTIVITY,MOLECULAR DOCKING,COUPLED RECEPTOR,DRUG DISCOVERY,TARGETING INHA,DATA-BANK,DESIGN},
  language     = {eng},
  number       = {24},
  pages        = {11069--11078},
  title        = {Discovery of mycobacterium tuberculosis InhA inhibitors by binding sites comparison and ligands prediction},
  url          = {http://dx.doi.org/10.1021/acs.jmedchem.6b01277},
  volume       = {59},
  year         = {2016},
}

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