title: Enabling the (3 + 2) cycloaddition reaction in assembling newer anti-tubercular lead acting through the inhibition of the gyrase ATPase domain: lead optimization and structure activity profiling.
abstract: DNA gyrase, the sole type II topoisomerase present in Mycobacterium tuberculosis, is absent in humans and is a well validated target for anti-tubercular drug discovery. In this study, a moderately active inhibitor of Mycobacterium tuberculosis GyrB, the pharmaceutically unexploited domain of DNA gyrase, was reengineered using a combination of molecular docking and medicinal chemistry strategies to obtain a lead series displaying considerable in vitro enzyme efficacy and bacterial kill against the Mycobacterium tuberculosis H37Rv strain. Biophysical investigations using differential scanning fluorimetry experiments re-ascertained the affinity of these molecules towards the GyrB domain. Furthermore, the molecules were completely devoid of hERG toxicity up to 30 μM, as evaluated in a zebra fish model with a good selectivity index, and from a pharmaceutical point of view, turned out as potential candidates against TB.
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 drdsriram@yahoo.com.
authors.forename: Variam Ullas
authors.initials: VU
authors.lastname: Jeankumar
authors.forename: Rudraraju Srilakshmi
authors.initials: RS
authors.lastname: Reshma
authors.forename: Renuka
authors.initials: R
authors.lastname: Janupally
authors.forename: Shalini
authors.initials: S
authors.lastname: Saxena
authors.forename: Jonnalagadda Padma
authors.initials: JP
authors.lastname: Sridevi
authors.forename: Brahmam
authors.initials: B
authors.lastname: Medapi
authors.forename: Pushkar
authors.initials: P
authors.lastname: Kulkarni
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003500:Cyclization; D027081:DNA Gyrase / Q000737:chemistry* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D023421:Models, Animal; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015027:Zebrafish
chemical_list: D000995:Antitubercular Agents; D059005:Topoisomerase II Inhibitors; D000251:Adenosine Triphosphatases; D027081:DNA Gyrase