连接器
硫酯酶
化学
组合化学
生物化学
计算机科学
酶
生物合成
操作系统
作者
Luís A. R. Carvalho,Bárbara B. Sousa,Daniel Zaidman,Hannah Kiely‐Collins,Gonçalo J. L. Bernardes
标识
DOI:10.1002/cbic.202300736
摘要
PROTAC linker design remains mostly an empirical task. We employed the PRosettaC computational software in the design of sulfonyl-fluoride-based PROTACs targeting acyl protein thioesterase 1 (APT1). The software efficiently generated ternary complex models from empirically-designed PROTACs and suggested alkyl linkers to be the preferred type of linker to target APT1. Western blotting analysis revealed efficient degradation of APT1 and activity-based protein profiling showed remarkable selectivity of an alkyl linker-based PROTAC amongst serine hydrolases. Collectively, our data suggests that combining PRosettaC and chemoproteomics can effectively assist in triaging PROTACs for synthesis and providing early data on their potency and selectivity.
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