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
-
- Animals
- Zebrafish/embryology
- Molecular Structure
- Embryo, Nonmammalian/drug effects
- DNA Gyrase/chemistry
- DNA Gyrase/drug effects*
- Adenosine Triphosphatases/chemistry
- Adenosine Triphosphatases/drug effects*
- Antitubercular Agents/chemistry
- Antitubercular Agents/pharmacology*
- 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??m], 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??m], 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