title: Gyrase ATPase domain as an antitubercular drug discovery platform: structure-based design and lead optimization of nitrothiazolyl carboxamide analogues.
abstract: In this study, we explored the pharmaceutically underexploited mycobacterial gyrase ATPase (GyrB) domain as a template for a structure-based virtual screening of our in-house (BITS Pilani) compound collection to discover new inhibitors targeting Mycobacterium tuberculosis (M.tb.) The hit identified was further customized by using a combination of molecular docking and medicinal chemistry strategies to obtain an optimized analogue displaying considerable in vitro enzyme efficacy and bactericidal properties against the M.tb. H37 Rv strain. The binding affinity of the ligand toward the GyrB domain was reascertained by differential scanning fluorimetry experiments. Further evaluation of the hERG toxicity (a major limitation among the previously reported N-linked aminopiperidine analogues) indicated these molecules to be completely devoid of cardiotoxicity, a significant achievement within this class.
authors: Department of Pharmacy, Birla Institute of Technology & Science Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh (India).
authors: Variam Ullas
authors: VU
authors: Jeankumar
authors: Janupally
authors: J
authors: Renuka
authors: Sonali
authors: S
authors: Kotagiri
authors: Shalini
authors: S
authors: Saxena
authors: Shruti Singh
authors: SS
authors: Kakan
authors: Jonnalagadda Padma
authors: JP
authors: Sridevi
authors: Swapna
authors: S
authors: Yellanki
authors: Pushkar
authors: P
authors: Kulkarni
authors: Perumal
authors: P
authors: Yogeeswari
authors: Dharmarajan
authors: D
authors: Sriram
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D027081:DNA Gyrase / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D006339:Heart Rate / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*; D015027:Zebrafish
chemical_list: D000577:Amides; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D013844:Thiazoles; D027081:DNA Gyrase
keywords: DNA gyrase; enzymes; inhibitors; tuberculosis; virtual screening