PUBLICATION
Structure-Guided Discovery of Antitubercular Agents That Target the Gyrase ATPase Domain
- Authors
- Jeankumar, V.U., Saxena, S., Vats, R., Reshma, R.S., Janupally, R., Kulkarni, P., Yogeeswari, P., Sriram, D.
- ID
- ZDB-PUB-170214-45
- Date
- 2016
- Source
- ChemMedChem 11: 539-48 (Journal)
- Registered Authors
- Kulkarni, Pushkar
- Keywords
- ATPase domain, DNA gyrase, Mycobacterium tuberculosis, Structure-based drug design, e-pharmacophores
- MeSH Terms
-
- Adenosine Triphosphatases/chemistry
- Adenosine Triphosphatases/drug effects*
- Animals
- Antitubercular Agents/chemistry
- Antitubercular Agents/pharmacology*
- DNA Gyrase/chemistry
- DNA Gyrase/drug effects*
- Embryo, Nonmammalian/drug effects
- Molecular Structure
- Zebrafish/embryology
- PubMed
- 26805396 Full text @ ChemMedChem.
Citation
Jeankumar, V.U., Saxena, S., Vats, R., Reshma, R.S., Janupally, R., Kulkarni, P., Yogeeswari, P., Sriram, D. (2016) Structure-Guided Discovery of Antitubercular Agents That Target the Gyrase ATPase Domain. ChemMedChem. 11:539-48.
Abstract
In this study we explored the pharmaceutically underexploited ATPase domain of DNA gyrase (GyrB) as a potential platform for developing novel agents that target Mycobacterium tuberculosis. In this effort a combination of ligand- and structure-based pharmacophore modeling was used to identify structurally diverse small-molecule inhibitors of the mycobacterial GyrB domain based on the crystal structure of the enzyme with a pyrrolamide inhibitor (PDB ID: 4BAE). Pharmacophore modeling and subsequent in vitro screening resulted in an initial hit compound 5 [(E)-5-(5-(2-(1H-benzo[d]imidazol-2-yl)-2-cyanovinyl)furan-2-yl)isophthalic acid; IC50 =4.6±0.1 μm], which was subsequently tailored through a combination of molecular modeling and synthetic chemistry to yield the optimized lead compound 24 [(E)-3-(5-(2-cyano-2-(5-methyl-1H-benzo[d]imidazol-2-yl)vinyl)thiophen-2-yl)benzoic acid; IC50 =0.3±0.2 μm], which was found to display considerable in vitro efficacy against the purified GyrB enzyme and potency against the H37 Rv strain of M. tuberculosis. Structural handles were also identified that will provide a suitable foundation for further optimization of these potent analogues.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping