Updating the portfolio of physicochemical descriptors related to permeability in the beyond the rule of 5 chemical space

Abstract

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 (pK_a measures and log k'80 PLRP-S trends), lipophilicity (in octanol/water, in apolar systems and in biomimetic environments), polarity (Δlog P_oct-tol, EPSA and Δlog K_W^IAM) 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 P_oct-tol and preliminary data support that chameleonicity could also have an impact.

Keywords: Beyond rule of 5; Chameleonicity; Ionization; Lipophilicity; Permeability; Polarity; Property-based drug design.