title: Structure-Guided Discovery of Antitubercular Agents That Target the Gyrase ATPase Domain.
abstract: 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 H37 Rv strain of M. tuberculosis. Structural handles were also identified that will provide a suitable foundation for further optimization of these potent analogues.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad, 500078, Andhra Pradesh, India.
authors.forename: Variam U
authors.initials: VU
authors.lastname: Jeankumar
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad, 500078, Andhra Pradesh, India.
authors.forename: Shalini
authors.initials: S
authors.lastname: Saxena
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad, 500078, Andhra Pradesh, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Vats
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad, 500078, Andhra Pradesh, India.
authors.forename: Rudraraju Srilakshmi
authors.initials: RS
authors.lastname: Reshma
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad, 500078, Andhra Pradesh, India.
authors.forename: Renuka
authors.initials: R
authors.lastname: Janupally
authors.affiliation: Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, 500046, India.|Zephase Therapeutics (an incubated company at Dr. Reddy's Institute of Life Sciences), University of Hyderabad Campus, Gachibowli, Hyderabad, 500046, India.
authors.forename: Pushkar
authors.initials: P
authors.lastname: Kulkarni
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad, 500078, Andhra Pradesh, India.
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad, 500078, Andhra Pradesh, India. dsriram@hyderabad.bits-pilani.ac.in.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000187:drug effects*; D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D027081:DNA Gyrase / Q000737:chemistry / Q000187:drug effects*; D004625:Embryo, Nonmammalian / Q000187:drug effects; D015394:Molecular Structure; D015027:Zebrafish / Q000196:embryology
chemical_list: D000995:Antitubercular Agents; D000251:Adenosine Triphosphatases; D027081:DNA Gyrase
keywords: ATPase domain; DNA gyrase; Mycobacterium tuberculosis; Structure-based drug design; e-pharmacophores