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

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

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.

• Jezik: Angleški jezik
• Ključne besede: thiazoles, hit profiling, promiscuous compounds, frequent hitters, privileged scaffolds, fragments
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2022
• Št. strani: Str. 1905–1910
• Številčenje: Vol. 13, iss. 12
• PID: 20.500.12556/RUL-143239
• UDK: 547.78:615.4:54
• ISSN pri članku: 1948-5875
• DOI: 10.1021/acsmedchemlett.2c00429
• COBISS.SI-ID: 130706947
• Datum objave v RUL: 09.12.2022

Gradivo je del revije

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

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: hit profiliranje, promiskuitetne spojine, pogosti napadalci, privilegirani odri, fragmenti, tiazoli, farmacevtska kemija