Structure-Guided Discovery of Antitubercular Agents That Target the Gyrase ATPase Domain
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- 作者：Dr. Variam U. Jeankumar ; Dr. Shalini Saxena ; Dr. Rahul Vats ; Rudraraju Srilakshmi Reshma ; Renuka Janupally ; Dr. Pushkar Kulkarni ; Prof. Perumal Yogeeswari and Prof. Dharmarajan Sriram
- 关键词：ATPase domain ; DNA gyrase ; e-pharmacophores ; Mycobacterium tuberculosis ; Structure-based drug design
- 刊名：ChemMedChem
- 出版年：2016
- 出版时间：March 4, 2016
- 年：2016
- 卷：11
- 期：5
- 页码：539-548
- 全文大小：1264K
- ISSN：1860-7187
文摘
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 H37Rv strain of M. tuberculosis. Structural handles were also identified that will provide a suitable foundation for further optimization of these potent analogues.