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- Title
Discovery of Novel Mycobacterial DNA Gyrase B Inhibitors: In Silico and In Vitro Biological Evaluation.
- Authors
Saxena, Shalini; Renuka, Janupally; Yogeeswari, Perumal; Sriram, Dharmarajan
- Abstract
DNA gyrase of Mycobacterium tuberculosis (MTB) is a type II topoisomerase that ensures the regulation of DNA topology and has been genetically demonstrated to be a bactericidal drug target. Availability of crystal structure of M. smegmatics GyrB in complex with one of the aminopyrazinamides facilitated us to employ structure-based virtual screening approach to obtain new hits from a commercial library of Asinex database using energy-optimized pharmacophore modeling. Further the model was validated using enrichment calculations, and finally three models were employed for high-throughput virtual screening and docking to identify novel DNA gyrase B inhibitors. This study led to the identification of fifteen potential compounds with IC50 values in the range of 1.5-45.5 µM against M. smegmatics GyrB and 1.16-25 µM in MTB supercoiling assay. Lead 11 emerged as the most potential compound, exhibiting inhibition of MTB DNA gyrase supercoiling with an IC50 of 1.16±0.25 µM, and M. smegmatics GyrB IC50 of 1.5±0.12 µM and hence could be further developed as novel inhibitor for mycobacterial GyrB.
- Subjects
DNA topoisomerase II; MYCOBACTERIUM tuberculosis; MYCOBACTERIAL disease treatment; MYCOBACTERIUM; THERAPEUTICS
- Publication
Molecular Informatics, 2014, Vol 33, Issue 9, p597
- ISSN
1868-1743
- Publication type
Article
- DOI
10.1002/minf.201400058