Fragment-sized thiazoles in fragment-based drug discovery campaigns : friend or foe?

Proj, Matic (author), Hrast, Martina (author), Knez, Damijan (author), Bozovičar, Krištof (author), Grabrijan, Katarina (author), Meden, Anže (author), Gobec, Stanislav (author), Frlan, Rok (author)

Thiazoles exhibit a wide range of biological activities and therefore represent useful and attractive building blocks. To evaluate their usefulness and pinpoint their liabilities in fragment screening campaigns, we assembled a focused library of 49 fragment-sized thiazoles and thiadiazoles with various substituents, namely amines, bromides, carboxylic acids, and nitriles. The library was profiled in a cascade of biochemical inhibition assays, redox activity, thiol reactivity, and stability assays. Our study indicates that when thiazole derivatives are identified as screening hits, their reactivity should be carefully addressed and correlated with specific on-target engagement. Importantly, nonspecific inhibition should be excluded using experimental approaches and in silico predictions. To help with validation of hits identified in fragment screening campaigns, we can apply our high-throughput profiling workflow to focus on the most tractable compounds with a clear mechanism of action.

• Language: English
• Keywords: thiazoles, hit profiling, promiscuous compounds, frequent hitters, privileged scaffolds, fragments
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2022
• Number of pages: Str. 1905–1910
• Numbering: Vol. 13, iss. 12
• PID: 20.500.12556/RUL-143239
• UDC: 547.78:615.4:54
• ISSN on article: 1948-5875
• DOI: 10.1021/acsmedchemlett.2c00429
• COBISS.SI-ID: 130706947
• Publication date in RUL: 09.12.2022

Record is a part of a journal

• Title: ACS medicinal chemistry letters
• Publisher: American Chemical Society
• ISSN: 1948-5875
• COBISS.SI-ID: 2959217

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.

Secondary language

• Language: Slovenian
• Keywords: hit profiliranje, promiskuitetne spojine, pogosti napadalci, privilegirani odri, fragmenti, tiazoli, farmacevtska kemija