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  2. Design, synthesis and biological evaluation of novel Pseudomonas aeruginosa DNA gyrase B inhibitors

Design, synthesis and biological evaluation of novel Pseudomonas aeruginosa DNA gyrase B inhibitors

  • Bioorg Chem. 2020 Jul;100:103905. doi: 10.1016/j.bioorg.2020.103905.
Sridhar Jogula 1 Vagolu Siva Krishna 1 Nikhila Meda 1 Vadla Balraju 2 Dharmarajan Sriram 3
Affiliations

Affiliations

  • 1 Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, India.
  • 2 Albany Molecular Research Hyderabad Research Centre Private Limited, MN Park, Genome valley, Hyderabad 500078, India.
  • 3 Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.
Abstract

In the present study, we attempted to develop a novel class of compounds active against Pseudomonas aeruginosa (Pa) by exploring the pharmaceutically well exploited Enzyme targets. Since, lack of Pa gyrase B crystal structures, Thermus thermophilus gyrase B in complex with novobiocin (1KIJ) was used as template to generate model structure by performing homology modeling. Further the best model was validated and used for high-throughput virtual screening, docking and dynamics simulations using the in-house database for identification of Pa DNA gyrase B inhibitors. This study led to an identification of three lead molecules with IC50 values in range of 6.25-15.6 µM against Pa gyrase supercoiling assay. Lead-1 optimization and expansion resulted in 15 compounds. Among the synthesized compounds six compounds were shown good Enzyme inhibition than Lead-1 (IC50 6.25 µM). Compound 13 emerged as the most potential compound exhibiting inhibition of Pa gyrase supercoiling with an IC50 of 2.2 µM; and in-vitro Pa activity with MIC of 8 µg/mL in presence of efflux pump inhibitor; hence could be further developed as novel inhibitor for Pa gyrase B.

Keywords

DNA gyrase B; Isothiazole; Molecular docking; Molecular dynamics; Oxazole; Pseudomonas aeruginosa.

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