A Genetic Algorithm Based Support Vector Machine Model for Blood-Brain Barrier Penetration Prediction

Abstract

Blood-brain barrier (BBB) is a highly complex physical barrier determining what substances are allowed to enter the brain. Support vector machine (SVM) is a kernel-based machine learning method that is widely used in QSAR study. For a successful SVM model, the kernel parameters for SVM and feature subset selection are the most important factors affecting prediction accuracy. In most studies, they are treated as two independent problems, but it has been proven that they could affect each other. We designed and implemented genetic algorithm (GA) to optimize kernel parameters and feature subset selection for SVM regression and applied it to the BBB penetration prediction. The results show that our GA/SVM model is more accurate than other currently available log BB models. Therefore, to optimize both SVM parameters and feature subset simultaneously with genetic algorithm is a better approach than other methods that treat the two problems separately. Analysis of our log BB model suggests that carboxylic acid group, polar surface area (PSA)/hydrogen-bonding ability, lipophilicity, and molecular charge play important role in BBB penetration. Among those properties relevant to BBB penetration, lipophilicity could enhance the BBB penetration while all the others are negatively correlated with BBB penetration.

Figure 1

Workflow of GA/SVM model for BBB penetration prediction.

Figure 2

Workflow of genetic algorithms.

Figure 3

Encoding of the chromosome.

Figure 4

Mating strategy of GA.

Figure 5

(a) Performance comparison of models with different number of features. (b) Evolution of the best 6-feature model.

Figure 6

Prediction accuracy of the final model on training set (a) and test set (b).

Figure 7

Top features for all 6-feature models (50 in all).

Figure 8

The most frequently used features for all top models.