QSAR modeling of the blood-brain barrier permeability for diverse organic compounds.

Purpose: Development of externally predictive Quantitative Structure-Activity Relationship (QSAR) models for Blood-Brain Barrier (BBB) permeability.

Methods: Combinatorial QSAR analysis was carried out for a set of 159 compounds with known BBB permeability data. All six possible combinations of three collections of descriptors derived from two-dimensional representations of molecules as chemical graphs and two QSAR methodologies have been explored. Descriptors were calculated by MolconnZ, MOE, and Dragon software. QSAR methodologies included k-Nearest Neighbors and Support Vector Machine approaches. All models have been rigorously validated using both internal and external validation methods.

Results: The consensus prediction for the external evaluation set afforded high predictive power (R2 = 0.80 for 10 compounds within the applicability domain after excluding one activity outlier). Classification accuracies for two additional external datasets, including 99 drugs and 267 organic compounds, classified as permeable (BBB+) or non-permeable (BBB-) were 82.5% and 59.0%, respectively. The use of a fairly conservative model applicability domain increased the prediction accuracy to 100% and 83%, respectively (while naturally reducing the dataset coverage to 60% and 43%, respectively). Important descriptors that affect BBB permeability are discussed.

Conclusion: Models developed in these studies can be used to estimate the BBB permeability of drug candidates at early stages of drug development.