RepurposeDrugs: an interactive web-portal and predictive platform for repurposing mono- and combination therapies.

RepurposeDrugs (https://repurposedrugs.org/) is a comprehensive web-portal that combines a unique drug indication database with a machine learning (ML) predictor to discover new drug-indication associations for approved as well as investigational mono and combination therapies. The platform provides detailed information on treatment status, disease indications and clinical trials across 25 indication categories, including neoplasms and cardiovascular conditions. The current version comprises 4314 compounds (approved, terminated or investigational) and 161 drug combinations linked to 1756 indications/conditions, totaling 28 148 drug-disease pairs. By leveraging data on both approved and failed indications, RepurposeDrugs provides ML-based predictions for the approval potential of new drug-disease indications, both for mono- and combinatorial therapies, demonstrating high predictive accuracy in cross-validation. The validity of the ML predictor is validated through a number of real-world case studies, demonstrating its predictive power to accurately identify repurposing candidates with a high likelihood of future approval. To our knowledge, RepurposeDrugs web-portal is the first integrative database and ML-based predictor for interactive exploration and prediction of both single-drug and combination approval likelihood across indications. Given its broad coverage of indication areas and therapeutic options, we expect it accelerates many future drug repurposing projects.

Fusing graph transformer with multi-aggregate GCN for enhanced drug-disease associations prediction.

BACKGROUND: Identification of potential drug-disease associations is important for both the discovery of new indications for drugs and for the reduction of unknown adverse drug reactions. Exploring the potential links between drugs and diseases is crucial for advancing biomedical research and improving healthcare. While advanced computational techniques play a vital role in revealing the connections between drugs and diseases, current research still faces challenges in the process of mining potential relationships between drugs and diseases using heterogeneous network data. RESULTS: In this study, we propose a learning framework for fusing Graph Transformer Networks and multi-aggregate graph convolutional network to learn efficient heterogenous information graph representations for drug-disease association prediction, termed WMAGT. This method extensively harnesses the capabilities of a robust graph transformer, effectively modeling the local and global interactions of nodes by integrating a graph convolutional network and a graph transformer with self-attention mechanisms in its encoder. We first integrate drug-drug, drug-disease, and disease-disease networks to construct heterogeneous information graph. Multi-aggregate graph convolutional network and graph transformer are then used in conjunction with neural collaborative filtering module to integrate information from different domains into highly effective feature representation. CONCLUSIONS: Rigorous cross-validation, ablation studies examined the robustness and effectiveness of the proposed method. Experimental results demonstrate that WMAGT outperforms other state-of-the-art methods in accurate drug-disease association prediction, which is beneficial for drug repositioning and drug safety research.

Examining the Potential of ChatGPT on Biomedical Information Retrieval: Fact-Checking Drug-Disease Associations.

Large language models (LLMs) such as ChatGPT have recently attracted significant attention due to their impressive performance on many real-world tasks. These models have also demonstrated the potential in facilitating various biomedical tasks. However, little is known of their potential in biomedical information retrieval, especially identifying drug-disease associations. This study aims to explore the potential of ChatGPT, a popular LLM, in discerning drug-disease associations. We collected 2694 true drug-disease associations and 5662 false drug-disease pairs. Our approach involved creating various prompts to instruct ChatGPT in identifying these associations. Under varying prompt designs, ChatGPT's capability to identify drug-disease associations with an accuracy of 74.6-83.5% and 96.2-97.6% for the true and false pairs, respectively. This study shows that ChatGPT has the potential in identifying drug-disease associations and may serve as a helpful tool in searching pharmacy-related information. However, the accuracy of its insights warrants comprehensive examination before its implementation in medical practice.

ITRPCA: a new model for computational drug repositioning based on improved tensor robust principal component analysis.

Background: Drug repositioning is considered a promising drug development strategy with the goal of discovering new uses for existing drugs. Compared with the experimental screening for drug discovery, computational drug repositioning offers lower cost and higher efficiency and, hence, has become a hot issue in bioinformatics. However, there are sparse samples, multi-source information, and even some noises, which makes it difficult to accurately identify potential drug-associated indications. Methods: In this article, we propose a new scheme with improved tensor robust principal component analysis (ITRPCA) in multi-source data to predict promising drug-disease associations. First, we use a weighted k-nearest neighbor (WKNN) approach to increase the overall density of the drug-disease association matrix that will assist in prediction. Second, a drug tensor with five frontal slices and a disease tensor with two frontal slices are constructed using multi-similarity matrices and an updated association matrix. The two target tensors naturally integrate multiple sources of data from the drug-side aspect and the disease-side aspect, respectively. Third, ITRPCA is employed to isolate the low-rank tensor and noise information in the tensor. In this step, an additional range constraint is incorporated to ensure that all the predicted entry values of a low-rank tensor are within the specific interval. Finally, we focus on identifying promising drug indications by analyzing drug-disease association pairs derived from the low-rank drug and low-rank disease tensors. Results: We evaluate the effectiveness of the ITRPCA method by comparing it with five prominent existing drug repositioning methods. This evaluation is carried out using 10-fold cross-validation and independent testing experiments. Our numerical results show that ITRPCA not only yields higher prediction accuracy but also exhibits remarkable computational efficiency. Furthermore, case studies demonstrate the practical effectiveness of our method.

Predicting Drug-Gene-Disease Associations by Tensor Decomposition for Network-Based Computational Drug Repositioning.

Drug repositioning offers the significant advantage of greatly reducing the cost and time of drug discovery by identifying new therapeutic indications for existing drugs. In particular, computational approaches using networks in drug repositioning have attracted attention for inferring potential associations between drugs and diseases efficiently based on the network connectivity. In this article, we proposed a network-based drug repositioning method to construct a drug-gene-disease tensor by integrating drug-disease, drug-gene, and disease-gene associations and predict drug-gene-disease triple associations through tensor decomposition. The proposed method, which ensembles generalized tensor decomposition (GTD) and multi-layer perceptron (MLP), models drug-gene-disease associations through GTD and learns the features of drugs, genes, and diseases through MLP, providing more flexibility and non-linearity than conventional tensor decomposition. We experimented with drug-gene-disease association prediction using two distinct networks created by chemical structures and ATC codes as drug features. Moreover, we leveraged drug, gene, and disease latent vectors obtained from the predicted triple associations to predict drug-disease, drug-gene, and disease-gene pairwise associations. Our experimental results revealed that the proposed ensemble method was superior for triple association prediction. The ensemble model achieved an AUC of 0.96 in predicting triple associations for new drugs, resulting in an approximately 7% improvement over the performance of existing models. It also showed competitive accuracy for pairwise association prediction compared with previous methods. This study demonstrated that incorporating genetic information leads to notable advancements in drug repositioning.

An effective multi-task learning framework for drug repurposing based on graph representation learning.

Drug repurposing, which typically applies the procedure of drug-disease associations (DDAs) prediction, is a feasible solution to drug discovery. Compared with traditional methods, drug repurposing can reduce the cost and time for drug development and advance the success rate of drug discovery. Although many methods for drug repurposing have been proposed and the obtained results are relatively acceptable, there is still some room for improving the predictive performance, since those methods fail to consider fully the issue of sparseness in known drug-disease associations. In this paper, we propose a novel multi-task learning framework based on graph representation learning to identify DDAs for drug repurposing. In our proposed framework, a heterogeneous information network is first constructed by combining multiple biological datasets. Then, a module consisting of multiple layers of graph convolutional networks is utilized to learn low-dimensional representations of nodes in the constructed heterogeneous information network. Finally, two types of auxiliary tasks are designed to help to train the target task of DDAs prediction in the multi-task learning framework. Comprehensive experiments are conducted on real data and the results demonstrate the effectiveness of the proposed method for drug repurposing.

Predicting Potential Drug-Disease Associations Based on Hypergraph Learning with Subgraph Matching.

The search for potential drug-disease associations (DDA) can speed up drug development cycles, reduce costly wasted resources, and accelerate disease treatment by repurposing existing drugs that can control further disease progression. As technologies such as deep learning continue to mature, many researchers tend to use emerging technologies to predict potential DDA. The performance of DDA prediction is still challenging and there is some space for improvement due to issues such as the small number of existing associations and possible noise in the data. To better predict DDA, we propose a computational approach based on hypergraph learning with subgraph matching (HGDDA). In particular, HGDDA first extracts feature subgraph information in the validated drug-disease association network and proposes a negative sampling strategy based on similarity network to reduce the data imbalance. Second, the hypergraph Unet module is used by extracting Finally, the potential DDA is predicted by designing a hypergraph combination module to convolution and pooling the two constructed hypergraphs separately, and calculating the difference information between the subgraphs using cosine similarity for node matching. The performance of HGDDA is verified under two standard datasets by 10-fold cross-validation (10-CV), and the results outperform existing drug-disease prediction methods. In addition, to validate the overall utility of the model, the top 10 drugs for the specific disease are predicted through the case study and validated using the CTD database.

Drug-Disease Association Prediction Using Heterogeneous Networks for Computational Drug Repositioning.

Drug repositioning, which involves the identification of new therapeutic indications for approved drugs, considerably reduces the time and cost of developing new drugs. Recent computational drug repositioning methods use heterogeneous networks to identify drug-disease associations. This review reveals existing network-based approaches for predicting drug-disease associations in three major categories: graph mining, matrix factorization or completion, and deep learning. We selected eleven methods from the three categories to compare their predictive performances. The experiment was conducted using two uniform datasets on the drug and disease sides, separately. We constructed heterogeneous networks using drug-drug similarities based on chemical structures and ATC codes, ontology-based disease-disease similarities, and drug-disease associations. An improved evaluation metric was used to reflect data imbalance as positive associations are typically sparse. The prediction results demonstrated that methods in the graph mining and matrix factorization or completion categories performed well in the overall assessment. Furthermore, prediction on the drug side had higher accuracy than on the disease side. Selecting and integrating informative drug features in drug-drug similarity measurement are crucial for improving disease-side prediction.

Teaching an old dog new tricks: Drug discovery by repositioning natural products and their derivatives.

Given the substantial cost and low success rate of drug discovery and development, repositioning existing drugs to treat new diseases has gained significant attention in recent years, with potentially lower development costs and shorter time frames. Natural products show great promise in drug repositioning because they have been used for various medical purposes for thousands of years. In this review, we discuss the drug repositioning of six prototypical natural products and their derivatives to reveal new drug-disease associations. We also highlight opportunities and challenges in natural product-based drug repositioning for future reference.

HINGRL: predicting drug-disease associations with graph representation learning on heterogeneous information networks.

Identifying new indications for drugs plays an essential role at many phases of drug research and development. Computational methods are regarded as an effective way to associate drugs with new indications. However, most of them complete their tasks by constructing a variety of heterogeneous networks without considering the biological knowledge of drugs and diseases, which are believed to be useful for improving the accuracy of drug repositioning. To this end, a novel heterogeneous information network (HIN) based model, namely HINGRL, is proposed to precisely identify new indications for drugs based on graph representation learning techniques. More specifically, HINGRL first constructs a HIN by integrating drug-disease, drug-protein and protein-disease biological networks with the biological knowledge of drugs and diseases. Then, different representation strategies are applied to learn the features of nodes in the HIN from the topological and biological perspectives. Finally, HINGRL adopts a Random Forest classifier to predict unknown drug-disease associations based on the integrated features of drugs and diseases obtained in the previous step. Experimental results demonstrate that HINGRL achieves the best performance on two real datasets when compared with state-of-the-art models. Besides, our case studies indicate that the simultaneous consideration of network topology and biological knowledge of drugs and diseases allows HINGRL to precisely predict drug-disease associations from a more comprehensive perspective. The promising performance of HINGRL also reveals that the utilization of rich heterogeneous information provides an alternative view for HINGRL to identify novel drug-disease associations especially for new diseases.

HeTDR: Drug repositioning based on heterogeneous networks and text mining.

Using existing knowledge to carry out drug-disease associations prediction is a vital method for drug repositioning. However, effectively fusing the biomedical text and biological network information is one of the great challenges for most current drug repositioning methods. In this study, we propose a drug repositioning method based on heterogeneous networks and text mining (HeTDR). This model can combine drug features from multiple drug-related networks, disease features from biomedical corpora with the known drug-disease associations network to predict the correlation scores between drug and disease. Experiments demonstrate that HeTDR has excellent performance that is superior to that of state-of-the-art models. We present the top 10 novel HeTDR-predicted approved drugs for five diseases and prove our model is capable of discovering potential candidate drugs for disease indications.

Drug repositioning based on similarity constrained probabilistic matrix factorization: COVID-19 as a case study.

The novel coronavirus disease 2019 (COVID-19) pandemic has caused a massive health crisis worldwide and upended the global economy. However, vaccines and traditional drug discovery for COVID-19 cost too much in terms of time, manpower, and money. Drug repurposing becomes one of the promising treatment strategies amid the COVID-19 crisis. At present, there are no publicly existing databases for experimentally supported human drug-virus interactions, and most existing drug repurposing methods require the rich information, which is not always available, especially for a new virus. In this study, on the one hand, we put size-able efforts to collect drug-virus interaction entries from literature and build the Human Drug Virus Database (HDVD). On the other hand, we propose a new approach, called SCPMF (similarity constrained probabilistic matrix factorization), to identify new drug-virus interactions for drug repurposing. SCPMF is implemented on an adjacency matrix of a heterogeneous drug-virus network, which integrates the known drug-virus interactions, drug chemical structures, and virus genomic sequences. SCPMF projects the drug-virus interactions matrix into two latent feature matrices for the drugs and viruses, which reconstruct the drug-virus interactions matrix when multiplied together, and then introduces the weighted similarity interaction matrix as constraints for drugs and viruses. Benchmarking comparisons on two different datasets demonstrate that SCPMF has reliable prediction performance and outperforms several recent approaches. Moreover, SCPMF-predicted drug candidates of COVID-19 also confirm the accuracy and reliability of SCPMF.

DDIT: An Online Predictor for Multiple Clinical Phenotypic Drug-Disease Associations.

Background: Drug repurposing provides an effective method for high-speed, low-risk drug development. Clinical phenotype-based screening exceeded target-based approaches in discovering first-in-class small-molecule drugs. However, most of these approaches predict only binary phenotypic associations between drugs and diseases; the types of drug and diseases have not been well exploited. Principally, the clinical phenotypes of a known drug can be divided into indications (Is), side effects (SEs), and contraindications (CIs). Incorporating these different clinical phenotypes of drug-disease associations (DDAs) can improve the prediction accuracy of the DDAs. Methods: We develop Drug Disease Interaction Type (DDIT), a user-friendly online predictor that supports drug repositioning by submitting known Is, SEs, and CIs for a target drug of interest. The dataset for Is, SEs, and CIs was extracted from PREDICT, SIDER, and MED-RT, respectively. To unify the names of the drugs and diseases, we mapped their names to the Unified Medical Language System (UMLS) ontology using Rest API. We then integrated multiple clinical phenotypes into a conditional restricted Boltzmann machine (RBM) enabling the identification of different phenotypes of drug-disease associations, including the prediction of as yet unknown DDAs in the input. Results: By 10-fold cross-validation, we demonstrate that DDIT can effectively capture the latent features of the drug-disease association network and represents over 0.217 and over 0.072 improvement in AUC and AUPR, respectively, for predicting the clinical phenotypes of DDAs compared with the classic K-nearest neighbors method (KNN, including drug-based KNN and disease-based KNN), Random Forest, and XGBoost. By conducting leave-one-drug-class-out cross-validation, the AUC and AUPR of DDIT demonstrated an improvement of 0.135 in AUC and 0.075 in AUPR compared to any of the other four methods. Within the top 10 predicted indications, side effects, and contraindications, 7/10, 9/10, and 9/10 hit known drug-disease associations. Overall, DDIT is a useful tool for predicting multiple clinical phenotypic types of drug-disease associations.

Computational drug repositioning based on multi-similarities bilinear matrix factorization.

With the development of high-throughput technology and the accumulation of biomedical data, the prior information of biological entity can be calculated from different aspects. Specifically, drug-drug similarities can be measured from target profiles, drug-drug interaction and side effects. Similarly, different methods and data sources to calculate disease ontology can result in multiple measures of pairwise disease similarities. Therefore, in computational drug repositioning, developing a dynamic method to optimize the fusion process of multiple similarities is a crucial and challenging task. In this study, we propose a multi-similarities bilinear matrix factorization (MSBMF) method to predict promising drug-associated indications for existing and novel drugs. Instead of fusing multiple similarities into a single similarity matrix, we concatenate these similarity matrices of drug and disease, respectively. Applying matrix factorization methods, we decompose the drug-disease association matrix into a drug-feature matrix and a disease-feature matrix. At the same time, using these feature matrices as basis, we extract effective latent features representing the drug and disease similarity matrices to infer missing drug-disease associations. Moreover, these two factored matrices are constrained by non-negative factorization to ensure that the completed drug-disease association matrix is biologically interpretable. In addition, we numerically solve the MSBMF model by an efficient alternating direction method of multipliers algorithm. The computational experiment results show that MSBMF obtains higher prediction accuracy than the state-of-the-art drug repositioning methods in cross-validation experiments. Case studies also demonstrate the effectiveness of our proposed method in practical applications. Availability: The data and code of MSBMF are freely available at https://github.com/BioinformaticsCSU/MSBMF. Corresponding author: Jianxin Wang, School of Computer Science and Engineering, Central South University, Changsha, Hunan 410083, P. R. China. E-mail: jxwang@mail.csu.edu.cn Supplementary Data: Supplementary data are available online at https://academic.oup.com/bib.

A Multi-Label Learning Framework for Drug Repurposing.

Drug repurposing plays an important role in screening old drugs for new therapeutic efficacy. The existing methods commonly treat prediction of drug-target interaction as a problem of binary classification, in which a large number of randomly sampled drug-target pairs accounting for over 50% of the entire training dataset are necessarily required. Such a large number of negative examples that do not come from experimental observations inevitably decrease the credibility of predictions. In this study, we propose a multi-label learning framework to find new uses for old drugs and discover new drugs for known target genes. In the framework, each drug is treated as a class label and its target genes are treated as the class-specific training data to train a supervised learning model of l2-regularized logistic regression. As such, the inter-drug associations are explicitly modelled into the framework and all the class-specific training data come from experimental observations. In addition, the data constraint is less demanding, for instance, the chemical substructures of a drug are no longer needed and the novel target genes are inferred only from the underlying patterns of the known genes targeted by the drug. Stratified multi-label cross-validation shows that 84.9% of known target genes have at least one drug correctly recognized, and the proposed framework correctly recognizes 86.73% of the independent test drug-target interactions (DTIs) from DrugBank. These results show that the proposed framework could generalize well in the large drug/class space without the information of drug chemical structures and target protein structures. Furthermore, we use the trained model to predict new drugs for the known target genes, identify new genes for the old drugs, and infer new associations between old drugs and new disease phenotypes via the OMIM database. Gene ontology (GO) enrichment analyses and the disease associations reported in recent literature provide supporting evidences to the computational results, which potentially shed light on new clinical therapies for new and/or old disease phenotypes.

Identification of Drug-Disease Associations Using Information of Molecular Structures and Clinical Symptoms via Deep Convolutional Neural Network.

Identifying drug-disease associations is helpful for not only predicting new drug indications and recognizing lead compounds, but also preventing, diagnosing, treating diseases. Traditional experimental methods are time consuming, laborious and expensive. Therefore, it is urgent to develop computational method for predicting potential drug-disease associations on a large scale. Herein, a novel method was proposed to identify drug-disease associations based on the deep learning technique. Molecular structure and clinical symptom information were used to characterize drugs and diseases. Then, a novel two-dimensional matrix was constructed and mapped to a gray-scale image for representing drug-disease association. Finally, deep convolution neural network was introduced to build model for identifying potential drug-disease associations. The performance of current method was evaluated based on the training set and test set, and accuracies of 89.90 and 86.51% were obtained. Prediction ability for recognizing new drug indications, lead compounds and true drug-disease associations was also investigated and verified by performing various experiments. Additionally, 3,620,516 potential drug-disease associations were identified and some of them were further validated through docking modeling. It is anticipated that the proposed method may be a powerful large scale virtual screening tool for drug research and development. The source code of MATLAB is freely available on request from the authors.

Predicting drug-disease associations by using similarity constrained matrix factorization.

BACKGROUND: Drug-disease associations provide important information for the drug discovery. Wet experiments that identify drug-disease associations are time-consuming and expensive. However, many drug-disease associations are still unobserved or unknown. The development of computational methods for predicting unobserved drug-disease associations is an important and urgent task. RESULTS: In this paper, we proposed a similarity constrained matrix factorization method for the drug-disease association prediction (SCMFDD), which makes use of known drug-disease associations, drug features and disease semantic information. SCMFDD projects the drug-disease association relationship into two low-rank spaces, which uncover latent features for drugs and diseases, and then introduces drug feature-based similarities and disease semantic similarity as constraints for drugs and diseases in low-rank spaces. Different from the classic matrix factorization technique, SCMFDD takes the biological context of the problem into account. In computational experiments, the proposed method can produce high-accuracy performances on benchmark datasets, and outperform existing state-of-the-art prediction methods when evaluated by five-fold cross validation and independent testing. CONCLUSION: We developed a user-friendly web server by using known associations collected from the CTD database, available at http://www.bioinfotech.cn/SCMFDD/ . The case studies show that the server can find out novel associations, which are not included in the CTD database.

DR2DI: a powerful computational tool for predicting novel drug-disease associations.

Finding the new related candidate diseases for known drugs provides an effective method for fast-speed and low-risk drug development. However, experimental identification of drug-disease associations is expensive and time-consuming. This motivates the need for developing in silico computational methods that can infer true drug-disease pairs with high confidence. In this study, we presented a novel and powerful computational tool, DR2DI, for accurately uncovering the potential associations between drugs and diseases using high-dimensional and heterogeneous omics data as information sources. Based on a unified and extended similarity kernel framework, DR2DI inferred the unknown relationships between drugs and diseases using Regularized Kernel Classifier. Importantly, DR2DI employed a semi-supervised and global learning algorithm which can be applied to uncover the diseases (drugs) associated with known and novel drugs (diseases). In silico global validation experiments showed that DR2DI significantly outperforms recent two approaches for predicting drug-disease associations. Detailed case studies further demonstrated that the therapeutic indications and side effects of drugs predicted by DR2DI could be validated by existing database records and literature, suggesting that DR2DI can be served as a useful bioinformatic tool for identifying the potential drug-disease associations and guiding drug repositioning. Our software and comparison codes are freely available at https://github.com/huayu1111/DR2DI .

Heter-LP: A heterogeneous label propagation algorithm and its application in drug repositioning.

Drug repositioning offers an effective solution to drug discovery, saving both time and resources by finding new indications for existing drugs. Typically, a drug takes effect via its protein targets in the cell. As a result, it is necessary for drug development studies to conduct an investigation into the interrelationships of drugs, protein targets, and diseases. Although previous studies have made a strong case for the effectiveness of integrative network-based methods for predicting these interrelationships, little progress has been achieved in this regard within drug repositioning research. Moreover, the interactions of new drugs and targets (lacking any known targets and drugs, respectively) cannot be accurately predicted by most established methods. In this paper, we propose a novel semi-supervised heterogeneous label propagation algorithm named Heter-LP, which applies both local and global network features for data integration. To predict drug-target, disease-target, and drug-disease associations, we use information about drugs, diseases, and targets as collected from multiple sources at different levels. Our algorithm integrates these various types of data into a heterogeneous network and implements a label propagation algorithm to find new interactions. Statistical analyses of 10-fold cross-validation results and experimental analyses support the effectiveness of the proposed algorithm.