Blood-Brain Barrier Permeation Models: Discriminating between Potential CNS and Non-CNS Drugs Including P-Glycoprotein Substrates

The aim of this article is to present the design of a large heterogeneous CNS library (∼1700 compounds)
from WDI and mapping CNS drugs using QSAR models of blood-brain barrier (BBB) permeation and P-gp
substrates. The CNS library finally includes 1336 BBB-crossing drugs (BBB+), 259 molecules non-BBB-crossing (BBB−), and 91 P-gp substrates (either BBB+ or BBB−). Discriminant analysis and PLS-DA
have been used to model the passive diffusion component of BBB permeation and potential physicochemical
requirement of P-gp substrates. Three categories of explanatory variables (Cdiff, BBBpred, PGPpred) have been
suggested to express the level of permeation within a continuous scale, starting from two classes data (BBB+/BBB−), allowing that the degree to which each compound belongs to an activity class is given using a
membership score. Finally, statistical data analyses have shown that some very simple descriptors are sufficient
to evaluate BBB permeation in most cases, with a high rate of well-classified drugs. Moreover, a “CNS
drugs” map, including P-gp substrates and accurately reflecting the in vivo behavior of drugs, is proposed
as a tool for CNS drug virtual screening.