title: Discovery of Novel Mycobacterial DNA Gyrase B Inhibitors: In Silico and In Vitro Biological Evaluation.
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.
authors.affiliation: D. Sriram, S. Saxena, J. Renuka, P. Yogeeswari, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, Andhra, Pradesh, India tel: +91-40663030506; fax: +91-4066303998.
authors.forename: Shalini
authors.initials: S
authors.lastname: Saxena
authors.affiliation: D. Sriram, S. Saxena, J. Renuka, P. Yogeeswari, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, Andhra, Pradesh, India tel: +91-40663030506; fax: +91-4066303998.
authors.forename: Janupally
authors.initials: J
authors.lastname: Renuka
authors.affiliation: D. Sriram, S. Saxena, J. Renuka, P. Yogeeswari, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, Andhra, Pradesh, India tel: +91-40663030506; fax: +91-4066303998.
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.affiliation: D. Sriram, S. Saxena, J. Renuka, P. Yogeeswari, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, Andhra, Pradesh, India tel: +91-40663030506; fax: +91-4066303998. dsriram@hyderabad.bits-pilani.ac.in, drdsriram@yahoo.com.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
keywords: DNA gyrase; Energy-optimized pharmacophore; Tuberculosis; Virtual screening