A comprehensive comparison of deep learning-based compound-target interaction prediction models to unveil guiding design principles

The evaluation of compound-target interactions (CTIs) is at the heart of drug discovery efforts. Given the substantial time and monetary costs of classical experimental screening, significant efforts have been dedicated to develop deep learning-based models that can accurately predict CTIs. A comprehensive comparison of these models on a large, curated CTI dataset is, however, still lacking. Here, we perform an in-depth comparison of 12 state-of-the-art deep learning architectures that use different protein and compound representations. The models were selected for their reported performance and architectures. To reliably compare model performance, we curated over 300 thousand binding and non-binding CTIs and established several gold-standard datasets of varying size and information. Based on our findings, DeepConv-DTI consistently outperforms other models in CTI prediction performance across the majority of datasets. It achieves an MCC of 0.6 or higher for most of the datasets and is one of the fastest models in training and inference. These results indicate that utilizing convolutional-based windows as in DeepConv-DTI to traverse trainable embeddings is a highly effective approach for capturing informative protein features. We also observed that physicochemical embeddings of targets increased model performance. We therefore modified DeepConv-DTI to include normalized physicochemical properties, which resulted in the overall best performing model Phys-DeepConv-DTI. This work highlights how the systematic evaluation of input features of compounds and targets, as well as their corresponding neural network architectures, can serve as a roadmap for the future development of improved CTI models.

Scientific contribution

This work features comprehensive CTI datasets to allow for the objective comparison and benchmarking of CTI prediction algorithms. Based on this dataset, we gained insights into which embeddings of compounds and targets and which deep learning-based algorithms perform best, providing a blueprint for the future development of CTI algorithms. Using the insights gained from this screen, we provide a novel CTI algorithm with state-of-the-art performance.