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Degraders early developability assessment: face-to-face with molecular properties.
Drug Discovery Today ( IF 7.4 ) Pub Date : 2020-06-18 , DOI: 10.1016/j.drudis.2020.06.015
Giuseppe Ermondi 1 , Maura Vallaro 1 , Giulia Caron 1
Affiliation  

Pharmaceutical scientists have huge expectations from heterobifunctional small molecule degraders to treat diseases with an unmet medical need. However, degraders are large and flexible and pose significant challenges in terms of cellular uptake and bioavailability. An efficient property-based design is therefore required to discover new oral degrader medicines. Here, we show the non‑transferability to degraders of in silico tools routinely implemented in small molecule drug discovery programs; and provide ionization, lipophilicity, polarity and chameleonicity data for a series of seven degraders. We also reveal that permeability can be modeled by Δlog kWIAM – an experimental polarity descriptor. Overall, the paper is a proof-of-concept that shows to discover new oral degrader drugs ad hoc property-based design strategies are required.



中文翻译:

降解物早期可开发性评估:与分子特性面对面。

制药科学家对异双功能小分子降解剂寄予厚望,以治疗医疗需求未得到满足的疾病。然而,降解剂体积大且灵活,在细胞摄取和生物利用度方面提出了重大挑战。因此,需要一种有效的基于特性的设计来发现新的口服降解药物。在这里,我们展示了在小分子药物发现计划中常规实施的计算机工具的降解剂的不可转移性;并提供一系列七种降解剂的电离、亲脂性、极性和变色性数据。我们还揭示了渗透率可以通过 Δlog k W IAM建模– 实验性极性描述符。总体而言,该论文是一个概念验证,表明需要基于特定特性的设计策略来发现新的口服降解药物。

更新日期:2020-06-18
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