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

Tanja Štular, Samo Lešnik, Kaja Rožman, Julia Schink, Mitja Zdouc, An Ghysels UGent, Feng Liu, Courtney C Aldrich, V Joachim Haupt, Sebastian Salentin, et al. (2016) JOURNAL OF MEDICINAL CHEMISTRY . 59(24). p.11069-11078
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
REDUCTASE FABI INHIBITORS, CARRIER PROTEIN REDUCTASE, ENOYL-ACP REDUCTASE, ANTIMYCOBACTERIAL ACTIVITY, MOLECULAR DOCKING, COUPLED RECEPTOR, DRUG DISCOVERY, TARGETING INHA, DATA-BANK, DESIGN
journal title
JOURNAL OF MEDICINAL CHEMISTRY
J. Med. Chem.
volume
59
issue
24
pages
11069 - 11078
Web of Science type
Article
Web of Science id
000390735500016
JCR category
CHEMISTRY, MEDICINAL
JCR impact factor
6.259 (2016)
JCR rank
3/60 (2016)
JCR quartile
1 (2016)
ISSN
0022-2623
1520-4804
DOI
10.1021/acs.jmedchem.6b01277
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
8501667
handle
http://hdl.handle.net/1854/LU-8501667
date created
2017-01-12 10:07:20
date last changed
2017-05-24 11:52:54
@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       = {\v{S}tular, Tanja and Le\v{s}nik, Samo and Ro\v{z}man, 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 Jane\v{z}i\v{c}, Du\v{s}anka and Konc, Janez},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY },
  keyword      = {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},
}

Chicago
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): 11069–11078.
APA
Štular, T., Lešnik, S., Rožman, K., Schink, J., Zdouc, M., Ghysels, A., Liu, F., et al. (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.
MLA
Štular, Tanja, Samo Lešnik, Kaja Rožman, et al. “Discovery of Mycobacterium Tuberculosis InhA Inhibitors by Binding Sites Comparison and Ligands Prediction.” JOURNAL OF MEDICINAL CHEMISTRY 59.24 (2016): 11069–11078. Print.