Department of Molecular Biotechnology and Health Sciences, University of Torino, Piazza Nizza 44bis, 10126 Torino, Italy.
Department of Chemistry - BMC, Uppsala University, SE-75123 Uppsala, Sweden.
Drug Discov Today. 2024 Apr;29(4):103917. doi: 10.1016/j.drudis.2024.103917. Epub 2024 Feb 14.
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.
在发现可口服的蛋白水解靶向嵌合体（PROTACs）作为药物时，主要面临的挑战是其生物利用度。因此，为了促进药物设计，识别更有可能具有口服生物利用度的 PROTAC 所在的化学空间至关重要。为此，我们使用传统的 2D 描述符从已发表的数据中提取结构-生物利用度的见解，从而阐明了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 描述符的前沿实验、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 的概率。
