DeepGRID: Deep Learning Using GRID Descriptors for BBB Prediction.

Deep Learning approaches are able to automatically extract relevant features from the input data and capture nonlinear relationships between the input and output. In this work, we present the GRID-derived AI (GrAId) descriptors, a simple modification to GRID MIFs that facilitate their use in combination with Convolutional Neural Networks (CNNs) to build Deep Learning models in a rotationally, conformationally, and alignment-independent approach we are calling DeepGRID. To our knowledge, this is the first time that GRID MIFs have been combined with CNNs in a Deep Learning approach. We applied the approach to build regression and classification models for blood-brain barrier permeation, an important factor when designing CNS drugs and conversely when designing to avoid off-target effects for CNS-inactive drugs. The VolSurf approach was one of the first to successfully model this property from three-dimensional structures, using descriptors derived from their GRID Molecular Interaction Fields (MIFs) in combination with PLS. We compared the DeepGRID models with others built using the hand-crafted VolSurf descriptors in combination with both PLS and Random Forest (RF). Both the DeepGRID and RF regression models performed best according to the % of compounds with a Geometric Mean Fold Error (GMFE) within 2-fold of the experimental data. Applying these regression models as classifiers, for the smaller 332 and 416 compound data sets all models performed well with ROC AUC values of ∼0.9 on the external test set. For the larger 2105 compound data set, the DeepGRID classifier performed the best with an AUC of 0.87 on the external test set with the RF model having an AUC of 0.84 and the original VolSurf lgBB model having an AUC of 0.83.