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Register a new userCASTER: Predicting Drug Interactions with Chemical Substructure Representation
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Adverse drug-drug interactions (DDIs) remain a leading cause of morbidity and mortality. Identifying potential DDIs during the drug design process is critical for patients and society. Although several computational models have been proposed for DDI prediction, there are still limitations: (1) specialized design of drug representation for DDI predictions is lacking; (2) predictions are based on limited labelled data and do not generalize well to unseen drugs or DDIs; and (3) models are characterized by a large number of parameters, thus are hard to interpret. In this work, we develop a ChemicAl SubstrucTurE Representation (CASTER) framework that predicts DDIs given chemical structures of drugs.CASTER aims to mitigate these limitations via (1) a sequential pattern mining module rooted in the DDI mechanism to efficiently characterize functional sub-structures of drugs; (2) an auto-encoding module that leverages both labelled and unlabelled chemical structure data to improve predictive accuracy and generalizability; and (3) a dictionary learning module that explains the prediction via a small set of coefficients which measure the relevance of each input sub-structures to the DDI outcome. We evaluated CASTER on two real-world DDI datasets and showed that it performed better than state-of-the-art baselines and provided interpretable predictions.
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Gaining more comprehensive knowledge about drug-drug interactions (DDIs) is one of the most important tasks in drug development and medical practice. Recently graph neural networks have achieved great success in this task by modeling drugs as nodes and drug-drug interactions as links and casting DDI predictions as link prediction problems. However, correlations between link labels (e.g., DDI types) were rarely considered in existing works. We propose the graph energy neural network (GENN) to explicitly model link type correlations. We formulate the DDI prediction task as a structure prediction problem and introduce a new energy-based model where the energy function is defined by graph neural networks. Experiments on two real-world DDI datasets demonstrated that GENN is superior to many baselines without consideration of link type correlations and achieved $13.77%$ and $5.01%$ PR-AUC improvement on the two datasets, respectively. We also present a case study in which mname can better capture meaningful DDI correlations compared with baseline models.
Drug combination therapy has become a increasingly promising method in the treatment of cancer. However, the number of possible drug combinations is so huge that it is hard to screen synergistic drug combinations through wet-lab experiments. Therefore, computational screening has become an important way to prioritize drug combinations. Graph neural network have recently shown remarkable performance in the prediction of compound-protein interactions, but it has not been applied to the screening of drug combinations. In this paper, we proposed a deep learning model based on graph neural networks and attention mechanism to identify drug combinations that can effectively inhibit the viability of specific cancer cells. The feature embeddings of drug molecule structure and gene expression profiles were taken as input to multi-layer feedforward neural network to identify the synergistic drug combinations. We compared DeepDDS with classical machine learning methods and other deep learning-based methods on benchmark data set, and the leave-one-out experimental results showed that DeepDDS achieved better performance than competitive methods. Also, on an independent test set released by well-known pharmaceutical enterprise AstraZeneca, DeepDDS was superior to competitive methods by more than 16% predictive precision. Furthermore, we explored the interpretability of the graph attention network, and found the correlation matrix of atomic features revealed important chemical substructures of drugs. We believed that DeepDDS is an effective tool that prioritized synergistic drug combinations for further wet-lab experiment validation.
In the past several months, COVID-19 has spread over the globe and caused severe damage to the people and the society. In the context of this severe situation, an effective drug discovery method to generate potential drugs is extremely meaningful. In this paper, we provide a methodology of discovering potential drugs for the treatment of Severe Acute Respiratory Syndrome Corona-Virus 2 (commonly known as SARS-CoV-2). We proposed a new model called Genetic Constrained Graph Variational Autoencoder (GCGVAE) to solve this problem. We trained our model based on the data of various viruses protein structure, including that of the SARS, HIV, Hep3, and MERS, and used it to generate possible drugs for SARS-CoV-2. Several optimization algorithms, including valency masking and genetic algorithm, are deployed to fine tune our model. According to the simulation, our generated molecules have great effectiveness in inhibiting SARS-CoV-2. We quantitatively calculated the scores of our generated molecules and compared it with the scores of existing drugs, and the result shows our generated molecules scores much better than those existing drugs. Moreover, our model can be also applied to generate effective drugs for treating other viruses given their protein structure, which could be used to generate drugs for future viruses.
Absorption, distribution, metabolism, and excretion (ADME) studies are critical for drug discovery. Conventionally, these tasks, together with other chemical property predictions, rely on domain-specific feature descriptors, or fingerprints. Following the recent success of neural networks, we developed Chemi-Net, a completely data-driven, domain knowledge-free, deep learning method for ADME property prediction. To compare the relative performance of Chemi-Net with Cubist, one of the popular machine learning programs used by Amgen, a large-scale ADME property prediction study was performed on-site at Amgen. The results showed that our deep neural network method improved current methods by a large margin. We foresee that the significantly increased accuracy of ADME prediction seen with Chemi-Net over Cubist will greatly accelerate drug discovery.
Off-the-shelf biomedical embeddings obtained from the recently released various pre-trained language models (such as BERT, XLNET) have demonstrated state-of-the-art results (in terms of accuracy) for the various natural language understanding tasks (NLU) in the biomedical domain. Relation Classification (RC) falls into one of the most critical tasks. In this paper, we explore how to incorporate domain knowledge of the biomedical entities (such as drug, disease, genes), obtained from Knowledge Graph (KG) Embeddings, for predicting Drug-Drug Interaction from textual corpus. We propose a new method, BERTKG-DDI, to combine drug embeddings obtained from its interaction with other biomedical entities along with domain-specific BioBERT embedding-based RC architecture. Experiments conducted on the DDIExtraction 2013 corpus clearly indicate that this strategy improves other baselines architectures by 4.1% macro F1-score.
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