title: Mycobacterial DNA gyrB inhibitors: Ligand based pharmacophore modelling and in vitro enzyme inhibition studies.
abstract: Among the topoisomerases, DNA gyrase belongs to the type II classes that catalysing DNA supercoiling or relaxation, catenation or decatenation, knotting or unknotting. It is one of the validated targets for anti-tubercular drug discovery and inhibitors from this group are also active against non-replicating, persistent mycobacteria, which might be important for shortening the duration of TB therapy. From past few years, extensive research was carried out towards potent DNA gyrase inhibitor design. The current review focuses on the most of potent series of DNA gyrase inhibitors and its structure activity relationships (SAR). The current manuscript also reports the current research on identification of potent DNA gyrase inhibitors using ligand based virtual screening approaches. The pharmacophore model was developed and validated against 65 known Mycobacterium smegmatics (MS) DNA Gyrase inhibitors. Validated pharmacophore model consists of HBA, HY, and RA features were essential for DNA Gyrase inhibition and this model was used to screen virtual screening to retrieve potential inhibitors from our in house database. Finally, 15 hits were ranked as potential leads based on pharmacophoric fit value and estimated activity. Furthermore, in-vitro enzymatic inhibition studies were performed for these 15 most promising candidates and these compounds were found to exhibit inhibition at 30 µM.
authors.forename: Shalini
authors.initials: S
authors.lastname: Saxena
authors.forename: Janupally
authors.initials: J
authors.lastname: Renuka
authors.forename: Variam Ullas
authors.initials: VU
authors.lastname: Jeankumar
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.affiliation: Computer Aided Drug Design Lab, 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: D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D027081:DNA Gyrase / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology / Q000254:growth & development*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase