Drug repositioning of herbal compounds via a machine-learning approach.
ABSTRACT: BACKGROUND:Drug repositioning, also known as drug repurposing, defines new indications for existing drugs and can be used as an alternative to drug development. In recent years, the accumulation of large volumes of information related to drugs and diseases has led to the development of various computational approaches for drug repositioning. Although herbal medicines have had a great impact on current drug discovery, there are still a large number of herbal compounds that have no definite indications. RESULTS:In the present study, we constructed a computational model to predict the unknown pharmacological effects of herbal compounds using machine learning techniques. Based on the assumption that similar diseases can be treated with similar drugs, we used four categories of drug-drug similarity (e.g., chemical structure, side-effects, gene ontology, and targets) and three categories of disease-disease similarity (e.g., phenotypes, human phenotype ontology, and gene ontology). Then, associations between drug and disease were predicted using the employed similarity features. The prediction models were constructed using classification algorithms, including logistic regression, random forest and support vector machine algorithms. Upon cross-validation, the random forest approach showed the best performance (AUC?=?0.948) and also performed well in an external validation assessment using an unseen independent dataset (AUC?=?0.828). Finally, the constructed model was applied to predict potential indications for existing drugs and herbal compounds. As a result, new indications for 20 existing drugs and 31 herbal compounds were predicted and validated using clinical trial data. CONCLUSIONS:The predicted results were validated manually confirming the performance and underlying mechanisms - for example, irinotecan as a treatment for neuroblastoma. From the prediction, herbal compounds were considered to be drug candidates for related diseases which is important to be further developed. The proposed prediction model can contribute to drug discovery by suggesting drug candidates from herbal compounds which have potentials but few were studied.
Project description:BACKGROUND:Drug repositioning is a promising and efficient way to discover new indications for existing drugs, which holds the great potential for precision medicine in the post-genomic era. Many network-based approaches have been proposed for drug repositioning based on similarity networks, which integrate multiple sources of drugs and diseases. However, these methods may simply view nodes as the same-typed and neglect the semantic meanings of different meta-paths in the heterogeneous network. Therefore, it is urgent to develop a rational method to infer new indications for approved drugs. RESULTS:In this study, we proposed a novel methodology named HeteSim_DrugDisease (HSDD) for the prediction of drug repositioning. Firstly, we build the drug-drug similarity network and disease-disease similarity network by integrating the information of drugs and diseases. Secondly, a drug-disease heterogeneous network is constructed, which combines the drug similarity network, disease similarity network as well as the known drug-disease association network. Finally, HSDD predicts novel drug-disease associations based on the HeteSim scores of different meta-paths. The experimental results show that HSDD performs significantly better than the existing state-of-the-art approaches. HSDD achieves an AUC score of 0.8994 in the leave-one-out cross validation experiment. Moreover, case studies for selected drugs further illustrate the practical usefulness of HSDD. CONCLUSIONS:HSDD can be an effective and feasible way to infer the associations between drugs and diseases using on meta-path-based semantic network analysis.
Project description:The application of established drug compounds to new therapeutic indications, known as drug repositioning, offers several advantages over traditional drug development, including reduced development costs and shorter paths to approval. Recent approaches to drug repositioning use high-throughput experimental approaches to assess a compound's potential therapeutic qualities. Here, we present a systematic computational approach to predict novel therapeutic indications on the basis of comprehensive testing of molecular signatures in drug-disease pairs. We integrated gene expression measurements from 100 diseases and gene expression measurements on 164 drug compounds, yielding predicted therapeutic potentials for these drugs. We recovered many known drug and disease relationships using computationally derived therapeutic potentials and also predict many new indications for these 164 drugs. We experimentally validated a prediction for the antiulcer drug cimetidine as a candidate therapeutic in the treatment of lung adenocarcinoma, and demonstrate its efficacy both in vitro and in vivo using mouse xenograft models. This computational method provides a systematic approach for repositioning established drugs to treat a wide range of human diseases.
Project description:Recently, the metabolite-likeness of the drug space has emerged and has opened a new possibility for exploring human metabolite-like candidates in drug discovery. However, the applicability of metabolite-likeness in drug discovery has been largely unexplored. Moreover, there are no reports on its applications for the repositioning of drugs to possible enzyme modulators, although enzyme-drug relations could be directly inferred from the similarity relationships between enzyme's metabolites and drugs.We constructed a drug-metabolite structural similarity matrix, which contains 1,861 FDA-approved drugs and 1,110 human intermediary metabolites scored with the Tanimoto similarity. To verify the metabolite-likeness measure for drug repositioning, we analyzed 17 known antimetabolite drugs that resemble the innate metabolites of their eleven target enzymes as the gold standard positives. Highly scored drugs were selected as possible modulators of enzymes for their corresponding metabolites. Then, we assessed the performance of metabolite-likeness with a receiver operating characteristic analysis and compared it with other drug-target prediction methods. We set the similarity threshold for drug repositioning candidates of new enzyme modulators based on maximization of the Youden's index. We also carried out literature surveys for supporting the drug repositioning results based on the metabolite-likeness.In this paper, we applied metabolite-likeness to repurpose FDA-approved drugs to disease-associated enzyme modulators that resemble human innate metabolites. All antimetabolite drugs were mapped with their known 11 target enzymes with statistically significant similarity values to the corresponding metabolites. The comparison with other drug-target prediction methods showed the higher performance of metabolite-likeness for predicting enzyme modulators. After that, the drugs scored higher than similarity score of 0.654 were selected as possible modulators of enzymes for their corresponding metabolites. In addition, we showed that drug repositioning results of 10 enzymes were concordant with the literature evidence.This study introduced a method to predict the repositioning of known drugs to possible modulators of disease associated enzymes using human metabolite-likeness. We demonstrated that this approach works correctly with known antimetabolite drugs and showed that the proposed method has better performance compared to other drug target prediction methods in terms of enzyme modulators prediction. This study as a proof-of-concept showed how to apply metabolite-likeness to drug repositioning as well as potential in further expansion as we acquire more disease associated metabolite-target protein relations.
Project description:Inferring potential drug indications, for either novel or approved drugs, is a key step in drug development. Previous computational methods in this domain have focused on either drug repositioning or matching drug and disease gene expression profiles. Here, we present a novel method for the large-scale prediction of drug indications (PREDICT) that can handle both approved drugs and novel molecules. Our method is based on the observation that similar drugs are indicated for similar diseases, and utilizes multiple drug-drug and disease-disease similarity measures for the prediction task. On cross-validation, it obtains high specificity and sensitivity (AUC=0.9) in predicting drug indications, surpassing existing methods. We validate our predictions by their overlap with drug indications that are currently under clinical trials, and by their agreement with tissue-specific expression information on the drug targets. We further show that disease-specific genetic signatures can be used to accurately predict drug indications for new diseases (AUC=0.92). This lays the computational foundation for future personalized drug treatments, where gene expression signatures from individual patients would replace the disease-specific signatures.
Project description:The traditional de novo drug discovery is known as a high cost and high risk process. In response, recently there is an increasing interest in discovering new indications for known drugs-a process known as drug repositioning-using computational methods. In this study, we present a new systematic approach for identifying potential new indications of an existing drug through its relation to similar drugs. Different from the previous similarity-based methods, we adapted a novel bipartite-graph based method when considering common drug targets and their interaction information. Furthermore, we added drug structure information into the calculation of drug pairwise similarity. In cross-validation experiments, our method achieved a sensitivity of 0.77 and specificity of 0.92 (AUC = 0.888) and compared favorably to the state of the art. When compared with a control group of drug uses, our drug repositioning results were found to be significantly enriched in both the biomedical literature and clinical trials. Our results indicate that combining chemical structure and drug target information results in better prediction performance and that the proposed approach successfully captures the implicit information between drug targets.
Project description:Drug repositioning is a cost-efficient and time-saving process to drug development compared to traditional techniques. A systematic method to drug repositioning is to identify candidate drug's gene expression profiles on target disease models and determine how similar these profiles are to approved drugs. Databases such as the CMAP have been developed recently to help with systematic drug repositioning.To overcome the limitation of connectivity maps on data coverage, we constructed a comprehensive in silico drug-protein connectivity map called DMAP, which contains directed drug-to-protein effects and effect scores. The drug-to-protein effect scores are compiled from all database entries between the drug and protein have been previously observed and provide a confidence measure on the quality of such drug-to-protein effects.In DMAP, we have compiled the direct effects between 24,121 PubChem Compound ID (CID), which were mapped from 289,571 chemical entities recognized from public literature, and 5,196 reviewed Uniprot proteins. DMAP compiles a total of 438,004 chemical-to-protein effect relationships. Compared to CMAP, DMAP shows an increase of 221 folds in the number of chemicals and 1.92 fold in the number of ATC codes. Furthermore, by overlapping DMAP chemicals with the approved drugs with known indications from the TTD database and literature, we obtained 982 drugs and 622 diseases; meanwhile, we only obtained 394 drugs with known indication from CMAP. To validate the feasibility of applying new DMAP for systematic drug repositioning, we compared the performance of DMAP and the well-known CMAP database on two popular computational techniques: drug-drug-similarity-based method with leave-one-out validation and Kolmogorov-Smirnov scoring based method. In drug-drug-similarity-based method, the drug repositioning prediction using DMAP achieved an Area-Under-Curve (AUC) score of 0.82, compared with that using CMAP, AUC = 0.64. For Kolmogorov-Smirnov scoring based method, with DMAP, we were able to retrieve several drug indications which could not be retrieved using CMAP. DMAP data can be queried using the existing C2MAP server or downloaded freely at: http://bio.informatics.iupui.edu/cmapsReliable measurements of how drug affect disease-related proteins are critical to ongoing drug development in the genome medicine era. We demonstrated that DMAP can help drug development professionals assess drug-to-protein relationship data and improve chances of success for systematic drug repositioning efforts.
Project description:Objective:Drug repositioning is a promising methodology for reducing the cost and duration of the drug discovery pipeline. We sought to develop a computational repositioning method leveraging annotations in the literature, such as Medical Subject Heading (MeSH) terms. Methods:We developed software to determine significantly co-occurring drug-MeSH term pairs and a method to estimate pair-wise literature-derived distances between drugs. Results:We found that literature-based drug-drug similarities predicted the number of shared indications across drug-drug pairs. Clustering drugs based on their similarity revealed both known and novel drug indications. We demonstrate the utility of our approach by generating repositioning hypotheses for the commonly used diabetes drug metformin. Conclusion:Our study demonstrates that literature-derived similarity is useful for identifying potential repositioning opportunities. We provided open-source code and deployed a free-to-use, interactive application to explore our database of similarity-based drug clusters (available at http://apps.chiragjpgroup.org/MeSHDD/ ).
Project description:Drug repositioning identifies new indications for known drugs. Here we report repositioning of the malaria drug amodiaquine as a potential anti-cancer agent. While most repositioning efforts emerge through serendipity, we have devised a computational approach, which exploits interaction patterns shared between compounds. As a test case, we took the anti-viral drug brivudine (BVDU), which also has anti-cancer activity, and defined ten interaction patterns using our tool PLIP. These patterns characterise BVDU's interaction with its target s. Using PLIP we performed an in silico screen of all structural data currently available and identified the FDA approved malaria drug amodiaquine as a promising repositioning candidate. We validated our prediction by showing that amodiaquine suppresses chemoresistance in a multiple myeloma cancer cell line by inhibiting the chaperone function of the cancer target Hsp27. This work proves that PLIP interaction patterns are viable tools for computational repositioning and can provide search query information from a given drug and its target to identify structurally unrelated candidates, including drugs approved by the FDA, with a known safety and pharmacology profile. This approach has the potential to reduce costs and risks in drug development by predicting novel indications for known drugs and drug candidates.
Project description:Discovering potential indications of novel or approved drugs is a key step in drug development. Previous computational approaches could be categorized into disease-centric and drug-centric based on the starting point of the issues or small-scaled application and large-scale application according to the diversity of the datasets. Here, a classifier has been constructed to predict the indications of a drug based on the assumption that interactive/associated drugs or drugs with similar structures are more likely to target the same diseases using a large drug indication dataset. To examine the classifier, it was conducted on a dataset with 1,573 drugs retrieved from Comprehensive Medicinal Chemistry database for five times, evaluated by 5-fold cross-validation, yielding five 1st order prediction accuracies that were all approximately 51.48%. Meanwhile, the model yielded an accuracy rate of 50.00% for the 1st order prediction by independent test on a dataset with 32 other drugs in which drug repositioning has been confirmed. Interestingly, some clinically repurposed drug indications that were not included in the datasets are successfully identified by our method. These results suggest that our method may become a useful tool to associate novel molecules with new indications or alternative indications with existing drugs.
Project description:Identification of potential drug-associated indications is critical for either approved or novel drugs in drug repositioning. Current computational methods based on drug similarity and disease similarity have been developed to predict drug-disease associations. When more reliable drug- or disease-related information becomes available and is integrated, the prediction precision can be continuously improved. However, it is a challenging problem to effectively incorporate multiple types of prior information, representing different characteristics of drugs and diseases, to identify promising drug-disease associations. In this study, we propose an overlap matrix completion (OMC) for bilayer networks (OMC2) and tri-layer networks (OMC3) to predict potential drug-associated indications, respectively. OMC is able to efficiently exploit the underlying low-rank structures of the drug-disease association matrices. In OMC2, first of all, we construct one bilayer network from drug-side aspect and one from disease-side aspect, and then obtain their corresponding block adjacency matrices. We then propose the OMC2 algorithm to fill out the values of the missing entries in these two adjacency matrices, and predict the scores of unknown drug-disease pairs. Moreover, we further extend OMC2 to OMC3 to handle tri-layer networks. Computational experiments on various datasets indicate that our OMC methods can effectively predict the potential drug-disease associations. Compared with the other state-of-the-art approaches, our methods yield higher prediction accuracy in 10-fold cross-validation and de novo experiments. In addition, case studies also confirm the effectiveness of our methods in identifying promising indications for existing drugs in practical applications.