Evaluation of Drug Efficacy Based on the Spatial Position Comparison of Drug-Target Interaction Centers: An Implication for Anticancer Drug Repositioning

2018 ◽  
Author(s):  
Yu Ding ◽  
Hong Wang ◽  
Hewei Zheng ◽  
Lianzong Wang ◽  
Guosi Zhang ◽  
...  
Keyword(s):  
Anticancer Drug ◽  
Drug Target ◽  
Drug Repositioning ◽  
Drug Efficacy ◽  
Spatial Position ◽  
Target Interaction

scholarly journals DLDTI: a learning-based framework for drug-target interaction identification using neural networks and network representation

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Yihan Zhao ◽  
Kai Zheng ◽  
Baoyi Guan ◽  
Mengmeng Guo ◽  
Lei Song ◽  
...  
Keyword(s):  
Neural Networks ◽  
Molecular Mechanism ◽  
Drug Target ◽  
Drug Repositioning ◽  
Biological Data ◽  
Mapping Space ◽  
Target Interaction ◽  
Network Representation ◽  
Combination Methods ◽  
Low Dimensional

Abstract Background Drug repositioning, the strategy of unveiling novel targets of existing drugs could reduce costs and accelerate the pace of drug development. To elucidate the novel molecular mechanism of known drugs, considering the long time and high cost of experimental determination, the efficient and feasible computational methods to predict the potential associations between drugs and targets are of great aid. Methods A novel calculation model for drug-target interaction (DTI) prediction based on network representation learning and convolutional neural networks, called DLDTI, was generated. The proposed approach simultaneously fused the topology of complex networks and diverse information from heterogeneous data sources, and coped with the noisy, incomplete, and high-dimensional nature of large-scale biological data by learning the low-dimensional and rich depth features of drugs and proteins. The low-dimensional feature vectors were used to train DLDTI to obtain the optimal mapping space and to infer new DTIs by ranking candidates according to their proximity to the optimal mapping space. More specifically, based on the results from the DLDTI, we experimentally validated the predicted targets of tetramethylpyrazine (TMPZ) on atherosclerosis progression in vivo. Results The experimental results showed that the DLDTI model achieved promising performance under fivefold cross-validations with AUC values of 0.9172, which was higher than the methods using different classifiers or different feature combination methods mentioned in this paper. For the validation study of TMPZ on atherosclerosis, a total of 288 targets were identified and 190 of them were involved in platelet activation. The pathway analysis indicated signaling pathways, namely PI3K/Akt, cAMP and calcium pathways might be the potential targets. Effects and molecular mechanism of TMPZ on atherosclerosis were experimentally confirmed in animal models. Conclusions DLDTI model can serve as a useful tool to provide promising DTI candidates for experimental validation. Based on the predicted results of DLDTI model, we found TMPZ could attenuate atherosclerosis by inhibiting signal transductions in platelets. The source code and datasets explored in this work are available at https://github.com/CUMTzackGit/DLDTI.

scholarly journals DLDTI: A learning-based framework for drug-target interaction identification using neural networks and network representation

2020 ◽  
Author(s):  
Yihan Zhao ◽  
Kai Zheng ◽  
Baoyi Guan ◽  
Mengmeng Guo ◽  
Lei Song ◽  
...  
Keyword(s):  
Neural Networks ◽  
Molecular Mechanism ◽  
Drug Target ◽  
Drug Repositioning ◽  
Biological Data ◽  
Mapping Space ◽  
Target Interaction ◽  
Network Representation ◽  
Combination Methods ◽  
Low Dimensional

Abstract Background: Drug repositioning, the strategy of unveiling novel targets of existing drugs could reduce costs and accelerate the pace of drug development. To elucidate the novel molecular mechanism of known drugs, considering the long time and high cost of experimental determination, the efficient and feasible computational methods to predict the potential associations between drugs and targets are of great aid.Methods: A novel calculation model for drug-target interaction (DTI) prediction based on network representation learning and convolutional neural networks, called DLDTI， was generated. The proposed approach simultaneously fuses the topology of complex networks and diverse information from heterogeneous data sources, and copes with the noisy, incomplete, and high-dimensional nature of large-scale biological data by learning the low-dimensional and rich depth features of drugs and proteins. The low-dimensional feature vectors were used to train DLDTI to obtain the optimal mapping space and to infer new DTIs by ranking candidates according to their proximity to the optimal mapping space. More specifically, based on the results from the DLDTI, we experimentally validate the predicted targets of tetramethylpyrazine (TMPZ) on atherosclerosis progression in vivo.Results: The experimental results show that the DLDTI model achieves promising performance under 5-fold cross-validations with AUC values of 0.9172, which is higher than the methods using different classifiers or different feature combination methods mentioned in this paper. For the validation study of TMPZ on atherosclerosis, a total of 288 targets were identified and 190 of them were involved in platelet activation. The pathway analysis indicated signaling pathways, namely PI3K/Akt, cAMP and calcium pathways might be the potential targets. Effects and molecular mechanism of TMPZ on atherosclerosis were experimentally confirmed in animal models.Conclusions: DLDTI model can serve as a useful tool to provide promising DTI candidates for experimental validation. Based on the predicted results of DLDTI model, we found TMPZ could attenuate atherosclerosis by inhibiting signal transductions in platelets. The source code and datasets explored in this work are available at https://github.com/CUMTzackGit/DLDTI.

scholarly journals A landscape for drug-target interactions based on network analysis

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0247018
Author(s):  
Edgardo Galan-Vasquez ◽  
Ernesto Perez-Rueda
Keyword(s):  
Drug Target ◽  
Target Genes ◽  
Metabolic Diseases ◽  
Drug Repositioning ◽  
Topological Analysis ◽  
Interaction Network ◽  
Clustering Coefficient ◽  
Connected Components ◽  
Target Interaction ◽  
Target Network

In this work, we performed an analysis of the networks of interactions between drugs and their targets to assess how connected the compounds are. For our purpose, the interactions were downloaded from the DrugBank database, and we considered all drugs approved by the FDA. Based on topological analysis of this interaction network, we obtained information on degree, clustering coefficient, connected components, and centrality of these interactions. We identified that this drug-target interaction network cannot be divided into two disjoint and independent sets, i.e., it is not bipartite. In addition, the connectivity or associations between every pair of nodes identified that the drug-target network is constituted of 165 connected components, where one giant component contains 4376 interactions that represent 89.99% of all the elements. In this regard, the histamine H1 receptor, which belongs to the family of rhodopsin-like G-protein-coupled receptors and is activated by the biogenic amine histamine, was found to be the most important node in the centrality of input-degrees. In the case of centrality of output-degrees, fostamatinib was found to be the most important node, as this drug interacts with 300 different targets, including arachidonate 5-lipoxygenase or ALOX5, expressed on cells primarily involved in regulation of immune responses. The top 10 hubs interacted with 33% of the target genes. Fostamatinib stands out because it is used for the treatment of chronic immune thrombocytopenia in adults. Finally, 187 highly connected sets of nodes, structured in communities, were also identified. Indeed, the largest communities have more than 400 elements and are related to metabolic diseases, psychiatric disorders and cancer. Our results demonstrate the possibilities to explore these compounds and their targets to improve drug repositioning and contend against emergent diseases.

scholarly journals DTI-SNNFRA: Drug-target interaction prediction by shared nearest neighbors and fuzzy-rough approximation

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246920
Author(s):  
Sk Mazharul Islam ◽  
Sk Md Mosaddek Hossain ◽  
Sumanta Ray
Keyword(s):  
Drug Discovery ◽  
Drug Target ◽  
Drug Repositioning ◽  
Geometric Mean ◽  
Imbalanced Data ◽  
Drug Repurposing ◽  
Search Space ◽  
Classification Model ◽  
Target Interaction ◽  
Rough Approximation

In-silico prediction of repurposable drugs is an effective drug discovery strategy that supplements de-nevo drug discovery from scratch. Reduced development time, less cost and absence of severe side effects are significant advantages of using drug repositioning. Most recent and most advanced artificial intelligence (AI) approaches have boosted drug repurposing in terms of throughput and accuracy enormously. However, with the growing number of drugs, targets and their massive interactions produce imbalanced data which may not be suitable as input to the classification model directly. Here, we have proposed DTI-SNNFRA, a framework for predicting drug-target interaction (DTI), based on shared nearest neighbour (SNN) and fuzzy-rough approximation (FRA). It uses sampling techniques to collectively reduce the vast search space covering the available drugs, targets and millions of interactions between them. DTI-SNNFRA operates in two stages: first, it uses SNN followed by a partitioning clustering for sampling the search space. Next, it computes the degree of fuzzy-rough approximations and proper degree threshold selection for the negative samples’ undersampling from all possible interaction pairs between drugs and targets obtained in the first stage. Finally, classification is performed using the positive and selected negative samples. We have evaluated the efficacy of DTI-SNNFRA using AUC (Area under ROC Curve), Geometric Mean, and F1 Score. The model performs exceptionally well with a high prediction score of 0.95 for ROC-AUC. The predicted drug-target interactions are validated through an existing drug-target database (Connectivity Map (Cmap)).

scholarly journals Drug-Target Interaction Prediction Based on Adversarial Bayesian Personalized Ranking

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Yihua Ye ◽  
Yuqi Wen ◽  
Zhongnan Zhang ◽  
Song He ◽  
Xiaochen Bo
Keyword(s):  
Partial Order ◽  
Matrix Factorization ◽  
Drug Target ◽  
Drug Repositioning ◽  
Expression Profiles ◽  
Learning To Rank ◽  
Prediction Performance ◽  
Target Interaction ◽  
Bayesian Personalized Ranking ◽  
Personalized Ranking

The prediction of drug-target interaction (DTI) is a key step in drug repositioning. In recent years, many studies have tried to use matrix factorization to predict DTI, but they only use known DTIs and ignore the features of drug and target expression profiles, resulting in limited prediction performance. In this study, we propose a new DTI prediction model named AdvB-DTI. Within this model, the features of drug and target expression profiles are associated with Adversarial Bayesian Personalized Ranking through matrix factorization. Firstly, according to the known drug-target relationships, a set of ternary partial order relationships is generated. Next, these partial order relationships are used to train the latent factor matrix of drugs and targets using the Adversarial Bayesian Personalized Ranking method, and the matrix factorization is improved by the features of drug and target expression profiles. Finally, the scores of drug-target pairs are achieved by the inner product of latent factors, and the DTI prediction is performed based on the score ranking. The proposed model effectively takes advantage of the idea of learning to rank to overcome the problem of data sparsity, and perturbation factors are introduced to make the model more robust. Experimental results show that our model could achieve a better DTI prediction performance.

scholarly journals Computational Discovery of Putative Leads for Drug Repositioning through Drug-Target Interaction Prediction

2016 ◽  
Vol 12 (11) ◽  
pp. e1005219 ◽  
Author(s):  
Edgar D. Coelho ◽  
Joel P. Arrais ◽  
José Luís Oliveira
Keyword(s):  
Drug Target ◽  
Drug Repositioning ◽  
Target Interaction ◽  
Interaction Prediction ◽  
Computational Discovery

Identification of Anticancer and Anti-inflammatory Drugs from Drug-target Interaction Descriptors by Machine Learning..

2022 ◽  
Vol 19 ◽  
Author(s):  
Songtao Huang ◽  
Yanrui Ding
Keyword(s):  
Machine Learning ◽  
Drug Target ◽  
Hydrophobic Interactions ◽  
Drug Repositioning ◽  
Limited Information ◽  
Target Interaction ◽  
Interaction Sites ◽  
Drug Classification ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Background: Drug repositioning is an important subject in drug-disease research. In the past, most studies simply used drug descriptors as the feature vector to classify drugs or targets, or used qualitative data about drug-target or drug-disease to predict drug-target interactions. These data provide limited information for drug repositioning. Objective: Considering both drugs and targets and constructing quantitative drug-target interaction descriptors as a method of drug characteristics are of great significance to the study of drug repositioning. Methods: Taking anticancer and anti-inflammatory drugs as research objects, the interaction sites between drugs and targets were determined by molecular docking. Sixty-seven drug-target interaction descriptors were calculated to describe the drug-target interactions, and 22 important descriptors were screened for drug classification by SVM, LightGBM and MLP. Results: The accuracy of SVM, LightGBM and MLP reached 93.29%, 92.68% and 94.51%, their Matthews correlation coefficients reached 0.852, 0.840 and 0.882, and their areas under the ROC curve reached 0.977, 0.969 and 0.968, respectively. Conclusion: Using drug-target interaction descriptors to build machine learning models can obtain better results for drug classification. Number of atom pairs, force field, hydrophobic interactions and bSASA are the four types of key features for the classification of anticancer and anti-inflammatory drugs.

Chemogenomic Approaches for Revealing Drug target Interactions in Drug Discovery

2021 ◽  
Vol 22 ◽  
Author(s):  
Harshita Bhargava ◽  
Amita Sharma ◽  
Prashanth Suravajhala
Keyword(s):  
Drug Discovery ◽  
In Silico ◽  
Drug Target ◽  
Drug Repositioning ◽  
Personalised Medicine ◽  
Classification Problem ◽  
Target Interaction ◽  
Advantages And Disadvantages

: The drug discovery process has been a crucial and cost-intensive process. This cost is not only monetary but also involves risks, time, and labour that are incurred while introducing a drug in the market. In order to reduce this cost and the risks associated with the drugs that may result in severe side effects, the in silico methods have gained popularity in recent years. These methods have had a significant impact on not only drug discovery but also the related areas such as drug repositioning, drug-target interaction prediction, drug side effect prediction, personalised medicine, etc. Amongst these research areas predicting interactions between drugs and targets forms the basis for drug discovery. The availability of big data in the form of bioinformatics, genetic databases, along with computational methods, have further supported data-driven decision-making. The results obtained through these methods may be further validated using in vitro or in vivo experiments. This validation step can further justify the predictions resulting from in silico approaches, further increasing the accuracy of the overall result in subsequent stages. A variety of approaches are used in predicting drug-target interactions, including ligand-based, molecular docking based and chemogenomic-based approaches. This paper discusses the chemogenomic methods, considering drug target interaction as a classification problem on whether or not an interaction between a particular drug and target would serve as a basis for understanding drug discovery/drug repositioning. We present the advantages and disadvantages associated with their application.

Evaluation of drug efficacy based on the spatial position comparison of drug–target interaction centers

2019 ◽  
Vol 21 (3) ◽  
pp. 762-776 ◽  
Author(s):  
Yu Ding ◽  
Hong Wang ◽  
Hewei Zheng ◽  
Lianzong Wang ◽  
Guosi Zhang ◽  
...  
Keyword(s):  
Drug Target ◽  
Spatial Position ◽  
Cancer Drugs ◽  
3 Dimensional ◽  
Target Interaction ◽  
Dimensional Interaction ◽  
Anti Cancer ◽  
Target Molecules ◽  
Interaction Center ◽  
Interaction Surface

Abstract The spatial position and interaction of drugs and their targets is the most important characteristics for understanding a drug’s pharmacological effect, and it could help both in finding new and more precise treatment targets for diseases and in exploring the targeting effects of the new drugs. In this work, we develop a computational pipeline to confirm the spatial interaction relationship of the drugs and their targets and compare the drugs’ efficacies based on the interaction centers. First, we produce a 100-sample set to reconstruct a stable docking model of the confirmed drug–target pairs. Second, we set 5.5 Å as the maximum distance threshold for the drug–amino acid residue atom interaction and construct 3-dimensional interaction surface models. Third, by calculating the spatial position of the 3-dimensional interaction surface center, we develop a comparison strategy for estimating the efficacy of different drug–target pairs. For the 1199 drug–target interactions of the 649 drugs and 355 targets, the drugs that have similar interaction center positions tend to have similar efficacies in disease treatment, especially in the analysis of the 37 targeted relationships between the 15 known anti-cancer drugs and 10 target molecules. Furthermore, the analysis of the unpaired anti-cancer drug and target molecules suggests that there is a potential application for discovering new drug actions using the sampling molecular docking and analyzing method. The comparison of the drug–target interaction center spatial position method better reflect the drug–target interaction situations and could support the discovery of new efficacies among the known anti-cancer drugs.

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