PUBLICATION
Enabling the (3 + 2) cycloaddition reaction in assembling newer anti-tubercular lead acting through the inhibition of the gyrase ATPase domain: lead optimization and structure activity profiling
- Authors
- Jeankumar, V.U., Reshma, R.S., Janupally, R., Saxena, S., Sridevi, J.P., Medapi, B., Kulkarni, P., Yogeeswari, P., Sriram, D.
- ID
- ZDB-PUB-170214-228
- Date
- 2015
- Source
- Organic & biomolecular chemistry 13: 2423-31 (Journal)
- Registered Authors
- Kulkarni, Pushkar
- Keywords
- none
- MeSH Terms
-
- Adenosine Triphosphatases/antagonists & inhibitors*
- Adenosine Triphosphatases/chemistry
- Adenosine Triphosphatases/metabolism
- Animals
- Antitubercular Agents/chemical synthesis
- Antitubercular Agents/chemistry
- Antitubercular Agents/pharmacology*
- Cell Line
- Cyclization
- DNA Gyrase/chemistry*
- DNA Gyrase/metabolism*
- Dose-Response Relationship, Drug
- Humans
- Mice
- Models, Animal
- Molecular Structure
- Mycobacterium tuberculosis/drug effects
- Mycobacterium tuberculosis/enzymology*
- Structure-Activity Relationship
- Topoisomerase II Inhibitors/chemical synthesis
- Topoisomerase II Inhibitors/chemistry
- Topoisomerase II Inhibitors/pharmacology*
- Zebrafish
- PubMed
- 25569565 Full text @ Org. Biomol. Chem.
Citation
Jeankumar, V.U., Reshma, R.S., Janupally, R., Saxena, S., Sridevi, J.P., Medapi, B., Kulkarni, P., Yogeeswari, P., Sriram, D. (2015) Enabling the (3 + 2) cycloaddition reaction in assembling newer anti-tubercular lead acting through the inhibition of the gyrase ATPase domain: lead optimization and structure activity profiling. Organic & biomolecular chemistry. 13:2423-31.
Abstract
DNA gyrase, the sole type II topoisomerase present in Mycobacterium tuberculosis, is absent in humans and is a well validated target for anti-tubercular drug discovery. In this study, a moderately active inhibitor of Mycobacterium tuberculosis GyrB, the pharmaceutically unexploited domain of DNA gyrase, was reengineered using a combination of molecular docking and medicinal chemistry strategies to obtain a lead series displaying considerable in vitro enzyme efficacy and bacterial kill against the Mycobacterium tuberculosis H37Rv strain. Biophysical investigations using differential scanning fluorimetry experiments re-ascertained the affinity of these molecules towards the GyrB domain. Furthermore, the molecules were completely devoid of hERG toxicity up to 30 μM, as evaluated in a zebra fish model with a good selectivity index, and from a pharmaceutical point of view, turned out as potential candidates against TB.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping