Drug–target interactions (DTIs) play a crucial role in target-based drug discovery and development. Computational prediction of DTIs can effectively complement experimental wet-lab techniques for the identification of DTIs, which are typically time- and resource-consuming. However, the performances of the current DTI prediction approaches suffer from a problem of low precision and high false-positive rate. In this study, we aim to develop a novel DTI prediction method for improving the prediction performance based on a cascade deep forest (CDF) model, named DTI-CDF, with multiple similarity-based features between drugs and the similarity-based features between target proteins extracted from the heterogeneous graph, which contains known DTIs. In the experiments, we built five replicates of 10-fold cross-validation under three different experimental settings of data sets, namely, corresponding DTI values of certain drugs (SD), targets (ST), or drug-target pairs (SP) in the training sets are missed but existed in the test sets. The experimental results demonstrate that our proposed approach DTI-CDF achieves a significantly higher performance than that of the traditional ensemble learning-based methods such as random forest and XGBoost, deep neural network, and the state-of-the-art methods such as DDR. Furthermore, there are 1352 newly predicted DTIs which are proved to be correct by KEGG and DrugBank databases. The data sets and source code are freely available at https://github.com//a96123155/DTI-CDF.

Drug discovery is an academical and commercial process of global importance. Accurate identification of drug-target interactions (DTIs) can significantly facilitate the drug discovery process. Compared to the costly, labor-intensive and time-consuming experimental methods, machine learning (ML) plays an ever-increasingly important role in effective, efficient and high-throughput identification of DTIs. However, upstream feature extraction methods require tremendous human resources and expert insights, which limits the application of ML approaches. Inspired by the unsupervised representation learning methods like Word2vec, we here proposed SPVec, a novel way to automatically represent raw data such as SMILES strings and protein sequences into continuous, information-rich and lower-dimensional vectors, so as to avoid the sparseness and bit collisions from the cumbersomely manually extracted features. Visualization of SPVec nicely illustrated that the similar compounds or proteins occupy similar vector space, which indicated that SPVec not only encodes compound substructures or protein sequences efficiently, but also implicitly reveals some important biophysical and biochemical patterns. Compared with manually-designed features like MACCS fingerprints and amino acid composition (AAC), SPVec showed better performance with several state-of-art machine learning classifiers such as Gradient Boosting Decision Tree, Random Forest and Deep Neural Network on BindingDB. The performance and robustness of SPVec were also confirmed on independent test sets obtained from DrugBank database. Also, based on the whole DrugBank dataset, we predicted the possibilities of all unlabeled DTIs, where two of the top five predicted novel DTIs were supported by external evidences. These results indicated that SPVec can provide an effective and efficient way to discover reliable DTIs, which would be beneficial for drug reprofiling.

A drug may be metabolized by multiple cytochrome P450 (CYP450) isoforms. Predicting the metabolic fate of drugs is very important to prevent drug− drug interactions in the development of novel pharmaceuticals. Prediction of CYP450 enzyme−substrate selectivity is formulized as a multilabel learning task in this study. First, we compared the performance of feature combinations based on four different categories of features, which are physiochemical property descriptors, mol2vec descriptors, extended connectivity fingerprints, and molecular access system key fingerprints on modeling. After identifying the best combination of features, we applied seven different multilabel models, which are multilabel k-nearest neighbor (ML-kNN), multilabel twin support vector machine, and five network-based label space division (NLSD)-based methods (NLSD-MLP, NLSD-XGB, NLSD-EXT, NLSD-RF, and NLSD-SVM). All of the six models (ML-kNN, NLSD-MLP, NLSD-XGB, NLSD-EXT, NLSD-RF, and NLSD-SVM) in this paper exhibit better performances than the previous work. Besides, NLSD-XGB achieves the best performance with the average top-1 prediction success of 91.1%, the average top-2 prediction success of 96.2%, and the average top-3 prediction success of 98.2%. When compared with the previous work, NLSD-XGB shows a significant improvement over 11% on top-1 in the 10 times repeated 5-fold cross-validation test and over 14% on top-1 in the 10 times repeated hold-out method. To the best of our knowledge, the network-based label space division model is first introduced in drug metabolism and performs well in this task.

G protein-coupled receptor 15 (GPR15, also known as BOB) is an extensively studied orphan G protein-coupled receptors (GPCRs) involving human immunodeficiency virus (HIV) infection, colonic inflammation, and smoking-related diseases. Recently, GPR15 was deorphanized and its corresponding natural ligand demonstrated an ability to inhibit cancer cell growth. However, no study reported the potential role of GPR15 in a pan-cancer manner. Using large-scale publicly available data from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases, we found that GPR15 expression is significantly lower in colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) than in normal tissues. Among 33 cancer types, GPR15 expression was significantly positively correlated with the prognoses of COAD, neck squamous carcinoma (HNSC), and lung adenocarcinoma (LUAD) and significantly negatively correlated with stomach adenocarcinoma (STAD). This study also revealed that commonly upregulated gene sets in the high GPR15 expression group (stratified via median) of COAD, HNSC, LUAD, and STAD are enriched in immune systems, indicating that GPR15 might be considered as a potential target for cancer immunotherapy. Furthermore, we modelled the 3D structure of GPR15 and conducted structure-based virtual screening. The top eight hit compounds were screened and then subjected to molecular dynamics (MD) simulation for stability analysis. Our study provides novel insights into the role of GPR15 in a pan-cancer manner and discovered a potential hit compound for GPR15 antagonists.

Anatomical Therapeutic Chemical (ATC) classification system proposed by the World Health Organization is a widely accepted drug classification scheme in both academic and industrial realm. It is a multilabeling system which categorizes drugs into multiple classes according to their therapeutic, pharmacological, and chemical attributes. In this study, we adopted a data-driven network-based label space partition (NLSP) method for prediction of ATC classes of a given compound within the multilabel learning framework. The proposed method ATC-NLSP is trained on the similarity-based features such as chemical–chemical interaction and structural and fingerprint similarities of a compound to other compounds belonging to the different ATC categories. The NLSP method trains predictors for each label cluster (possibly intersecting) detected by community detection algorithms and takes the ensemble labels for a compound as final prediction. Experimental evaluation based on the jackknife test on the benchmark dataset demonstrated that our method has boosted the absolute true rate, which is the most stringent evaluation metrics in this study, from 0.6330 to 0.7497, in comparison to the state-of-the-art approaches. Moreover, the community structures of the label relation graph were detected through the label propagation method. The advantage of multilabel learning over the single-label models was shown by label-wise analysis. Our study indicated that the proposed method ATC-NLSP, which adopts ideas from network research community and captures the correlation of labels in a data driven manner, is the top-performing model in the ATC prediction task. We believed that the power of NLSP remains to be unleashed for the multilabel learning tasks in drug discovery. The source codes are freely available at .