Discovery of Novel Mycobacterial DNA Gyrase B Inhibitors: In Silico and In Vitro Biological Evaluation

作者：Saxena Shalini^*; Renuka Janupally; Yogeeswari Perumal; Sriram Dharmarajan

来源：Molecular Informatics, 2014, 33(9): 597-609.

DOI：10.1002/minf.201400058

• Tuberculosis
• DNA gyrase
• Energy-optimized pharmacophore
• Virtual screening

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 mu M against M. smegmatics GyrB and 1.16-25 mu M 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 mu M, and M. smegmatics GyrB IC50 of 1.5 +/- 0.12 mu M and hence could be further developed as novel inhibitor for mycobacterial GyrB.

• 出版日期2014-9