Beyond rule of 5 (bRo5) molecules are attracting significant interest in modern drug discovery mostly because many novel targets require large and more flexible structures. The main aim of this paper is the identification of ad hoc bRo5 physicochemical descriptors of ionization, lipophilicity, polarity and chameleonicity and their measurement. We used different methods to collect ionization (pKa measures and log k'80 PLRP-S trends), lipophilicity (in octanol/water, in apolar systems and in biomimetic environments), polarity (Δlog Poct-tol, EPSA and Δlog KWIAM) and chameleonicity (ChameLogD) descriptors for 26 bRo5 drugs. A second aim was to check the relationship between physicochemical descriptors and permeability for a subset of compounds for which solid permeability values are reported in the literature. Results showed that the physicochemical profile in the bRo5 chemical space is often experimentally accessible, albeit more tools are required to overcome limitations of individual methods. For the investigated compounds, permeability is governed by Δlog Poct-tol and preliminary data support that chameleonicity could also have an impact.

中文翻译：

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在5化学空间规则之外，更新与渗透性相关的物理化学描述符组合。

超越5（bRo5）规则的分子在现代药物发现中引起了极大的兴趣，这主要是因为许多新型靶标都需要更大且更灵活的结构。本文的主要目的是鉴定电离，亲脂性，极性和化学性的特异bRo5理化指标及其测量。我们使用了不同的方法来收集电离（pKa度量和log k'80 PLRP-S趋势），亲脂性（在辛醇/水中，在非极性系统和仿生环境中），极性（ΔlogPoct-tol，EPSA和ΔlogKWIAM）和26种bRo5药物的chameleonicity（ChameLogD）描述符。第二个目的是检查在文献中报道了固体渗透率值的化合物子集的理化指标与渗透率之间的关系。结果表明，尽管需要更多工具来克服各个方法的局限性，但bRo5化学空间中的理化概况通常可以通过实验获得。对于所研究的化合物，通透性受ΔlogPoct-tol的控制，初步数据表明，化学通性也可能产生影响。