The identification of drug-target relations (DTRs) is substantial in drug development. A large number of methods treat DTRs as drug-target interactions (DTIs), a binary classification problem. The main drawback of these methods are the lack of reliable negative samples and the absence of many important aspects of DTR, including their dose dependence and quantitative affinities. With increasing number of publications of drug-protein binding affinity data recently, DTRs prediction can be viewed as a regression problem of drug-target affinities (DTAs) which reflects how tightly the drug binds to the target and can present more detailed and specific information than DTIs. The growth of affinity data enables the use of deep learning architectures, which have been shown to be among the state-of-the-art methods in binding affinity prediction. Although relatively effective, due to the black-box nature of deep learning, these models are less biologically interpretable. In this study, we proposed a deep learning-based model, named AttentionDTA, which uses attention mechanism to predict DTAs. Different from the models using 3D structures of drug-target complexes or graph representation of drugs and proteins, the novelty of our work is to use attention mechanism to focus on key subsequences which are important in drug and protein sequences when predicting its affinity. We use two separate one-dimensional Convolution Neural Networks (1D-CNNs) to extract the semantic information of drug's SMILES string and protein's amino acid sequence. Furthermore, a two-side multi-head attention mechanism is developed and embedded to our model to explore the relationship between drug features and protein features. We evaluate our model on three established DTA benchmark datasets, Davis, Metz, and KIBA. AttentionDTA outperforms the state-of-the-art deep learning methods under different evaluation metrics. The results show that the attention-based model can effectively extract protein features related to drug information and drug features related to protein information to better predict drug target affinities. It is worth mentioning that we test our model on IC50 dataset, which provides the binding sites between drugs and proteins, to evaluate the ability of our model to locate binding sites. Finally, we visualize the attention weight to demonstrate the biological significance of the model. The source code of AttentionDTA can be downloaded from https://github.com/zhaoqichang/AttentionDTA_TCBB.

MOTIVATION: Identifying drug-target interactions is a crucial step for drug discovery and design. Traditional biochemical experiments are credible to accurately validate drug-target interactions. However, they are also extremely laborious, time-consuming and expensive. With the collection of more validated biomedical data and the advancement of computing technology, the computational methods based on chemogenomics gradually attract more attention, which guide the experimental verifications. RESULTS: In this study, we propose an end-to-end deep learning-based method named IIFDTI to predict drug-target interactions (DTIs) based on independent features of drug-target pairs and interactive features of their substructures. First, the interactive features of substructures between drugs and targets are extracted by the bidirectional encoder-decoder architecture. The independent features of drugs and targets are extracted by the graph neural networks and convolutional neural networks, respectively. Then, all extracted features are fused and inputted into fully connected dense layers in downstream tasks for predicting DTIs. IIFDTI takes into account the independent features of drugs/targets and simulates the interactive features of the substructures from the biological perspective. Multiple experiments show that IIFDTI outperforms the state-of-the-art methods in terms of the area under the receiver operating characteristics curve (AUC), the area under the precision-recall curve (AUPR), precision, and recall on benchmark datasets. In addition, the mapped visualizations of attention weights indicate that IIFDTI has learned the biological knowledge insights, and two case studies illustrate the capabilities of IIFDTI in practical applications. AVAILABILITY AND IMPLEMENTATION: The data and codes underlying this article are available in Github at https://github.com/czjczj/IIFDTI. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Identifying drug-target interactions (DTIs) is an important step in the process of new drug discovery and drug repositioning. Accurate predictions for DTIs can improve the efficiency in the drug discovery and development. Although rapid advances in deep learning technologies have generated various computational methods, it is still appealing to further investigate how to design efficient networks for predicting DTIs. In this study, we propose an end-to-end deep learning method (called MHSADTI) to predict DTIs based on the graph attention network and multi-head self-attention mechanism. First, the characteristics of drugs and proteins are extracted by the graph attention network and multi-head self-attention mechanism, respectively. Then, the attention scores are used to consider which amino acid subsequence in a protein is more important for the drug to predict its interactions. Finally, we predict DTIs by a fully connected layer after obtaining the feature vectors of drugs and proteins. MHSADTI takes advantage of self-attention mechanism for obtaining long-dependent contextual relationship in amino acid sequences and predicting DTI interpretability. More effective molecular characteristics are also obtained by the attention mechanism in graph attention networks. Multiple cross validation experiments are adopted to assess the performance of our MHSADTI. The experiments on four datasets, human, C.elegans, DUD-E and DrugBank show our method outperforms the state-of-the-art methods in terms of AUC, Precision, Recall, AUPR and F1-score. In addition, the case studies further demonstrate that our method can provide effective visualizations to interpret the prediction results from biological insights.

The identification of compound-protein relations (CPRs), which includes compound-protein interactions (CPIs) and compound-protein affinities (CPAs), is critical to drug development. A common method for compound-protein relation identification is the use of in vitro screening experiments. However, the number of compounds and proteins is massive, and in vitro screening experiments are labor-intensive, expensive, and time-consuming with high failure rates. Researchers have developed a computational field called virtual screening (VS) to aid experimental drug development. These methods utilize experimentally validated biological interaction information to generate datasets and use the physicochemical and structural properties of compounds and target proteins as input information to train computational prediction models. At present, deep learning has been widely used in computer vision and natural language processing and has experienced epoch-making progress. At the same time, deep learning has also been used in the field of biomedicine widely, and the prediction of CPRs based on deep learning has developed rapidly and has achieved good results. The purpose of this study is to investigate and discuss the latest applications of deep learning techniques in CPR prediction. First, we describe the datasets and feature engineering (i.e., compound and protein representations and descriptors) commonly used in CPR prediction methods. Then, we review and classify recent deep learning approaches in CPR prediction. Next, a comprehensive comparison is performed to demonstrate the prediction performance of representative methods on classical datasets. Finally, we discuss the current state of the field, including the existing challenges and our proposed future directions. We believe that this investigation will provide sufficient references and insight for researchers to understand and develop new deep learning methods to enhance CPR predictions.