A BOILED-Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules

Abstract

Apart from efficacy and toxicity, many drug development failures are imputable to poor pharmacokinetics and bioavailability. Gastrointestinal absorption and brain access are two pharmacokinetic behaviors crucial to estimate at various stages of the drug discovery processes. To this end, the Brain Or IntestinaL EstimateD permeation method (BOILED-Egg) is proposed as an accurate predictive model that works by computing the lipophilicity and polarity of small molecules. Concomitant predictions for both brain and intestinal permeation are obtained from the same two physicochemical descriptors and straightforwardly translated into molecular design, owing to the speed, accuracy, conceptual simplicity and clear graphical output of the model. The BOILED-Egg can be applied in a variety of settings, from the filtering of chemical libraries at the early steps of drug discovery, to the evaluation of drug candidates for development.

Keywords: blood-brain barrier; chemoinformatics; drug absorption; medicinal chemistry; physicochemical properties.

Figure 1

Overview of the BOILED‐Egg construction. a) Gastrointestinal absorption and b) brain penetration datasets (HIA and BBB in Tables S1 and S2, respectively) cleansed, neutralized, standardized, converted into SMILES notation were subject to lipophilicity (WLOGP) and polarity (tPSA) computation. Best classification ellipse for well‐ and poorly absorbed molecules (blue points and green squares, respectively, in (c) and Figure S1) as well as for brain penetrant and non‐penetrant molecules (pink points and brown squares, respectively, in (d) and Figure S2). e) Combining both best ellipses yields the BOILED‐Egg predictive model. The white region is the physicochemical space of molecules with highest probability of being absorbed by the gastrointestinal tract, and the yellow region (yolk) is the physicochemical space of molecules with highest probability to permeate to the brain. Yolk and white areas are not mutually exclusive.

Figure 2

Test and illustrative uses of the BOILED‐Egg. a) Plot of 46 compounds accepted as NCEs by the FDA in 2014 and 2015 (FDA dataset in Table S5). Well‐ and poorly absorbed molecules (blue points and green squares, respectively) are predicted with an accuracy of 83 % (three true negatives (TN) are outside the range). Drugs with good evidence of brain access are circled in red. b) Optimization path of BCR‐ABL inhibitors leading to the oral anticancer drug ponatinib (in blue) and optimization path of AMPA receptor modulators leading to a brain penetrant investigational drug under clinical evaluation (in pink). Chemical structures and a more detailed description are provided in Figures S9 and S10.