A principal challenge in the discovery of proteolysis targeting chimeras (PROTACs) as oral medications is their bioavailability. To facilitate drug design, it is therefore essential to identify the chemical space where orally bioavailable PROTACs are more likely to be situated. To this aim, we extracted structure-bioavailability insights from published data using traditional 2D descriptors, thereby shedding light on their potential and limitations as drug design tools. Subsequently, we describe cutting-edge experimental, computational and hybrid design strategies based on 3D descriptors, which show promise for enhancing the probability of discovering PROTACs with high oral bioavailability.

中文翻译：

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探索口服生物可利用的 PROTAC 的化学空间

发现作为口服药物的蛋白水解靶向嵌合体（PROTAC）的主要挑战是其生物利用度。因此，为了促进药物设计，有必要确定口服生物可利用的 PROTAC 更可能位于的化学空间。为此，我们使用传统的二维描述符从已发表的数据中提取结构生物利用度见解，从而揭示它们作为药物设计工具的潜力和局限性。随后，我们描述了基于 3D 描述符的尖端实验、计算和混合设计策略，这些策略有望提高发现具有高口服生物利用度的 PROTAC 的可能性。