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Tuning Properties for Blood–Brain Barrier Permeation: A Statistics-Based Analysis

2019; American Chemical Society; Volume: 11; Issue: 1 Linguagem: Inglês

10.1021/acschemneuro.9b00541

1948-7193

Maria Dichiara, Benedetto Amata, Rita Turnaturi, Agostino Marrazzo, Emanuele Amata,

Molecular Sensors and Ion Detection

In the effort to define a set of rules useful in tuning the properties for a successful blood–brain barrier (BBB) permeation, we statistically analyzed a set of 328 compounds and correlated their experimental in vivo logBB with a series of computed descriptors. Contingency tables were constructed, observed and expected distributions were calculated, and chi-square (χ2) distributions were evaluated. This allowed to point out a significant dependence of certain physicochemical properties in influencing the BBB permeation. Of over 15 computed descriptors, 9 resulted to be particularly important showing highly significant χ2 distribution: polar surface area (χ2 = 66.79; p = 1.08 × 10−13), nitrogen and oxygen count (χ2 = 51.17; p = 2.06 × 10−10), logP (χ2 = 47.38; p = 1.27 × 10–9), nitrogen count (χ2 = 38.29; p = 9.77 × 10−8), logD (χ2 = 36.80; p = 36.80), oxygen count (χ2 = 35.83; p = 3.13 × 10−7), ionization state (χ2 = 33.02, p = 3.19 × 10−7), hydrogen bond acceptors (χ2 = 30.80; p = 3.36 × 10−6), and hydrogen bond donors (χ2 = 29.29; p = 6.81 × 10–6). Other parameters describing the mass and size of the molecules (molecular weight: 11.18; p = 2.46 × 10–2) resulted in being not significant since the population within the observed and expected distribution was similar. Depending on the combination of the significant descriptors, we set a three cases probabilistic scenario (BBB+, BBB–, BBB+/BBB–) that would prospectively be used to tune properties for BBB permeation.