Selective DNA gyrase inhibitors : multi-target in silico profiling with 3D-pharmacophores

Tomašič, Tihomir (author), Zubrienė, Asta (author), Skok, Žiga (author), Martini, Riccardo (author), Pajk, Stane (author), Sosič, Izidor (author), Ilaš, Janez (author), Matulis, Daumantas (author), Bryant, Sharon D. (author)

DNA gyrase is an important target for the development of novel antibiotics. Although ATP-competitive DNA gyrase (GyrB) inhibitors are a well-studied class of antibacterial agents, there is currently no representative used in therapy, largely due to unwanted off-target activities. Selectivity of GyrB inhibitors against closely related human ATP-binding enzymes should be evaluated early in development to avoid off-target binding to homologous binding domains. To address this challenge, we developed selective 3D-pharmacophore models for GyrB, human topoisomerase IIα (TopoII), and the Hsp90 N-terminal domain (NTD) to be used in in silico activity profiling paradigms to identify molecules selective for GyrB over TopoII and Hsp90, as starting points for hit expansion and lead optimization. The models were used to profile highly active GyrB, TopoII, and Hsp90 inhibitors. Selected compounds were tested in in vitro assays. GyrB inhibitors 1 and 2 were inactive against TopoII and Hsp90, while 3 and 4, potent Hsp90 inhibitors, displayed no inhibition of GyrB and TopoII, and TopoII inhibitors 5 and 6 were inactive at GyrB and Hsp90. The results provide a proof of concept for the use of target activity profiling methods to identify selective starting points for hit and lead identification.

• Language: English
• Keywords: antibacterial, ATP-competitive, DNA gyrase, Hsp90, pharmacophore model, topoisomerase II, target activity profiling, topoisomerase IIα
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: 24 str.
• Numbering: Vol. 14, iss. 8, art. 789
• PID: 20.500.12556/RUL-135975
• UDC: 546.96:547.8
• ISSN on article: 1424-8247
• DOI: 10.3390/ph14080789
• COBISS.SI-ID: 73095939
• Publication date in RUL: 05.04.2022

Record is a part of a journal

• Title: Pharmaceuticals
• Shortened title: Pharmaceuticals
• Publisher: MDPI
• ISSN: 1424-8247
• COBISS.SI-ID: 517582617

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 10.08.2021

Secondary language

• Language: Slovenian
• Keywords: protibakterijsko delovanje, farmakoforni model, topoizomeraza IIα, tarčna aktivnost, zaviralci, farmacevtska kemija