Abstract

Context: This study investigates the potential of leveraging molecular properties, as determined by MD-LOVIs software and machine learning techniques, to predict the ability of compounds to cross the blood–brain barrier (BBB). Accurate prediction of BBB permeation is critical for the development of central nervous system (CNS) drugs. The study applies various machine learning models, including both classification and regression techniques, to predict BBB passage and molecular activity. Notably, classification models such as GBM-AWV (accuracy = 0.801), GLM-CN (accuracy = 0.808), SVMPoly-means (accuracy = 0.980), SVMPoly-AC (accuracy = 0.980), SVMPoly-MI_TI_SI (accuracy = 0.900), SVMPoly-GI (accuracy = 0.900), RF-means (accuracy = 0.870), and GLM-means (accuracy = 0.818) demonstrate high accuracy in predicting BBB passage. In contrast, regression models like ES-RLM-AG (R2 = 0.902), IB-IBK (R2 = 0.82), IB-Kstar (R2 = 0.834), IB-MLP (R2 = 0.843), and DRF-AWV (R2 = 0.810) exhibit strong performance in predicting molecular activity. The results show that classification models like GBM-AWV, GLM-CN, and SVMPoly variants, as well as regression models like ES-RLM-AG and IB-MLP, achieve high performance, demonstrating the effectiveness of machine learning in predicting BBB permeability. Methods: The computational methods employed in this study include the MD-LOVIs software for generating molecular descriptors and several machine learning algorithms, including gradient boosting machines (GBM), generalized linear models (GLM), support vector machines (SVM) with polynomial kernels, random forests (RF), ensemble regression models, and instance-based learning algorithms. These models were trained and validated using various datasets to predict BBB passage and molecular activity, with the performance metrics reported for each model. Standard computational techniques were employed throughout, ensuring the reliability of the predictions. Graphical Abstract: (Figure presented.) © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.