KekuleScope: prediction of cancer cell line sensitivity and compound potency using convolutional neural networks...

The application of convolutional neural networks (ConvNets) to harness high-content screening images or 2D compound representations is gaining increasing attention in drug discovery. However, existing applications often require large data sets for training, or sophisticated pretraining schemes. Here, we show using 33 IC₅₀ data sets from ChEMBL 23 that the in vitro activity of compounds on cancer cell lines and protein targets can be accurately predicted on a continuous scale from their Kekulé structure representations alone by extending existing architectures (AlexNet, DenseNet-201, ResNet152 and VGG-19), which were pretrained on unrelated image data sets. We show that the predictive power of the generated models, which just require standard 2D compound representations as input, is comparable to that of Random Forest (RF) models and fully-connected Deep Neural Networks trained on circular (Morgan) fingerprints. Notably, including additional fully-connected layers further increases the predictive power of the ConvNets by up to 10%. Analysis of the predictions generated by RF models and ConvNets shows that by simply averaging the output of the RF models and ConvNets we obtain significantly lower errors in prediction for multiple data sets, although the effect size is small, than those obtained with either model alone, indicating that the features extracted by the convolutional layers of the ConvNets provide complementary predictive signal to Morgan fingerprints. Lastly, we show that multi-task ConvNets trained on compound images permit to model COX isoform selectivity on a continuous scale with errors in prediction comparable to the uncertainty of the data. Overall, in this work we present a set of ConvNet architectures for the prediction of compound activity from their Kekulé structure representations with state-of-the-art performance, that require no generation of compound descriptors or use of sophisticated image processing techniques. The code needed to reproduce the results presented in this study and all the data sets are provided at https://github.com/isidroc/kekulescope .