Fragment-sized thiazoles in fragment-based drug discovery campaigns

friend or foe?

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

Povzetek

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.

Ključne besede

thiazoles;hit profiling;promiscuous compounds;frequent hitters;privileged scaffolds;fragments;

Podatki

Jezik:	Angleški jezik
Leto izida:	2022
Tipologija:	1.01 - Izvirni znanstveni članek
Organizacija:	UL FFA - Fakulteta za farmacijo
UDK:	547.78:615.4:54
COBISS:	130706947
ISSN:	1948-5875
Št. ogledov:	91
Št. prenosov:	52
Ocena:	0 (0 glasov)
Metapodatki:

Ostali podatki

Sekundarni jezik:	Slovenski jezik
Sekundarne ključne besede:	hit profiliranje;promiskuitetne spojine;pogosti napadalci;privilegirani odri;fragmenti;Tiazoli;Farmacevtska kemija;
Vrsta dela (COBISS):	Članek v reviji
Strani:	str. 1905–1910
Letnik:	ǂVol. ǂ13
Zvezek:	ǂiss. ǂ12
Čas izdaje:	2022
DOI:	10.1021/acsmedchemlett.2c00429
ID:	17361116