title: Engineering another class of anti-tubercular lead: Hit to lead optimization of an intriguing class of gyrase ATPase inhibitors.
abstract: A structure based medium throughput virtual screening campaign of BITS-Pilani in house chemical library to identify novel binders of Mycobacterium tuberculosis gyrase ATPase domain led to the discovery of a quinoline scaffold. Further medicinal chemistry explorations on the right hand core of the early hit, engendered a potent lead demonstrating superior efficacy both in the enzyme and whole cell screening assay. The binding affinity shown at the enzyme level was further corroborated by biophysical characterization techniques. Early pharmacokinetic evaluation of the optimized analogue was encouraging and provides interesting potential for further optimization.
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 Ullas
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: 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: 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: Renuka
authors.initials: R
authors.lastname: Janupally
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: 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. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D027081:DNA Gyrase / Q000737:chemistry / Q000378:metabolism*; D055808:Drug Discovery; D004738:Engineering; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D011487:Protein Conformation
chemical_list: D000995:Antitubercular Agents; D000251:Adenosine Triphosphatases; D027081:DNA Gyrase
keywords: DNA gyrase; Differential scanning fluorimetry; Medium throughput virtual screening; Mycobacterium tuberculosis