SimBoost: a readacross approach for predicting drug–target binding affinities using gradient boosting machines
 Tong He†^{1},
 Marten Heidemeyer†^{1},
 Fuqiang Ban^{2},
 Artem Cherkasov†^{2} and
 Martin Ester†^{1}Email authorView ORCID ID profile
Received: 3 November 2016
Accepted: 30 March 2017
Published: 18 April 2017
Abstract
Computational prediction of the interaction between drugs and targets is a standing challenge in the field of drug discovery. A number of rather accurate predictions were reported for various binary drug–target benchmark datasets. However, a notable drawback of a binary representation of interaction data is that missing endpoints for noninteracting drug–target pairs are not differentiated from inactive cases, and that predicted levels of activity depend on predefined binarization thresholds. In this paper, we present a method called SimBoost that predicts continuous (nonbinary) values of binding affinities of compounds and proteins and thus incorporates the whole interaction spectrum from true negative to true positive interactions. Additionally, we propose a version of the method called SimBoostQuant which computes a prediction interval in order to assess the confidence of the predicted affinity, thus defining the Applicability Domain metrics explicitly. We evaluate SimBoost and SimBoostQuant on two established drug–target interaction benchmark datasets and one new dataset that we propose to use as a benchmark for readacross cheminformatics applications. We demonstrate that our methods outperform the previously reported models across the studied datasets.
Keywords
Readacross Gradient boosting Drug–target interaction Prediction interval Applicability Domain QSARBackground
Finding a compound that selectively binds to a particular protein is a highly challenging and typically expensive procedure in the drug development process, where more than 90% of candidate compounds fail due to crossreactivity and/or toxicity issues. It is therefore an important topic in drug research to gain knowledge about the interaction of compounds and target proteins through computational methods. Such in silico approaches are capable of speeding up the experimental wet lab work by systematically prioritizing the most potent compounds and help predicting their potential side effects.
Recent studies [1] have demonstrated that machine learningbased approaches have the potential to predict compoundprotein interactions on a large scale by learning from limited interaction data supplemented with information on the similarity among compounds and among proteins. Incorporating the similarity between drugs and between targets to infer the interaction of untested drug–target pairs is the essence of the readacross methodology [2].
The datasets commonly used for the training and evaluation of such machine learningbased prediction methods are the Enzymes, Ion Channels, Nuclear Receptor, and G ProteinCoupled Receptor datasets [3]. These datasets contain binary labels \(Y_{(i,j)} = 1\) if drug–target pair \((d_{i} ,t_{j} )\) is known to interact (as shown by wet lab experiments) and \(Y_{(i,j)} = 0\) if either \((d_{i} ,t_{j} )\) is known to not interact or if the interaction of \((d_{i} ,t_{j} )\) is unknown. The datasets tend to be biased towards drugs and targets that are considered to be more important or easier to test experimentally. As elaborated in [4], the use of such binary datasets has two major limitations: (1) truenegative interactions and missing values are not differentiated, and (2) a given compoundtarget interaction is treated as a binary on–off relationship, although it is more informative to use a continuous value that quantifies how strongly a compound binds to a target.
The study of [4] introduces two continuous interaction datasets and the continuous evaluation metric \(CI\) and presents a readacross method KronRLS which predicts continuous binding affinities. The prediction in KronRLS is based on a similarity score for each drug–target pair, where the similarity of drug–target pairs is defined through the Kronecker product of a drug–drug similarity matrix and a target–target similarity matrix. Another method that has previously been shown to achieve high performance in drug target interaction prediction is Matrix Factorization (MF) [5–7], which in its simplest formulation learns to predict drug target interaction just from the given binding values without incorporating similarity information among drugs and among targets.
Intuitively both KronRLS and MF share the limitation of capturing only linear dependencies in the training data. To the best of our knowledge, no nonlinear methods for drug–target interaction prediction have been presented in the literature. Furthermore, we believe that due to the biased nature of the training datasets it is necessary to assign a confidence score to a prediction. As emphasized in [8] it is important to address the uncertainty of the predictions of readacross approaches, but previous methods have neglected this need.
In this paper, we propose a novel nonlinear method, SimBoost, for continuous drug–target binding affinity prediction, and a version SimBoostQuant, using quantile regression to estimate a prediction interval as a measure of confidence. Given a training dataset of continuous binding affinities and the similarities among drugs and among targets, SimBoost constructs features for drugs, targets, and drug–target pairs, and uses gradient boosting machines to predict the binding affinity for a drug–target pair and to generate a prediction interval. Besides gradient boosting, another nonlinear method that can predict the value of some dependent variable and generate a prediction interval is random forests [9]. We have two reasons for choosing gradient boosting over random forests. First, all the trees in a random forest can be seen as identically distributed. Thus, if their prediction is biased then the average of the prediction is also biased, which may lead to a less accurate final result. Second, the random forest algorithm for quantile regression introduced in [9] produces the same tree structure as the usual random forest algorithm and only changes the way in which predictions are generated for the leaf nodes. This implies that the trees are not grown in a shape optimized for quantile regression. Our proposed gradient boosting method overcomes both limitations.
Gradient boosting machines have been employed in previous QSAR studies [10, 11]. Svetnik et al. [11] compares the performance of gradient boosting machines against commonly used QSAR methods such as support vector machines for regression and classification problems involving only compounds. Singh and Shikha [10] utilizes gradient boosting machines to predict toxic effects of nanomaterials. In both studies, gradient boosting machines show promising results in terms of prediction performance, speed and robustness. A major difference of our work compared to these previous studies is the problem formulation: In [10, 11] a prediction is made for a single entity (nanomaterial or compound), and descriptors for the compounds/nanomaterials are given. In the drug–target setting, on the other hand, we make predictions for pairs of entities, i.e. one drug and one target. Therefore, we present a novel feature engineering step on which our method relies in the learning and prediction phases.
Related work
Traditional methods for drug target interaction prediction typically focus on one particular target of interest. These approaches can again be divided into two types which are targetbased approaches [12–14] and ligandbased approaches [15–18]. In targetbased approaches the molecular docking of a candidate compound with the protein target is simulated, based on the 3D structure of the target (and the compound). This approach is widely utilized to virtually screen compounds against target proteins; however this approach is not applicable when the 3D structure of a target protein is not available which is often the case, especially for Gprotein coupled receptors and ion channels. The intuition in ligandbased methods is to model the common characteristics of a target, based on its known interacting ligands (compounds). One interesting example for this approach is the study [4] which utilizes similarities in the sideeffects of known drugs to predict new drug–target interactions. However, the ligandbased approach may not work well if the number of known interacting ligands of a protein target is small.
To allow more efficient predictions on a larger scale, i.e. for many targets simultaneously, and to overcome the limitations of the traditional methods, machine learning based approaches have attracted much attention recently. In the chemical and biologicals sciences, machine learningbased approaches have been known as (multitarget) Quantitative structure–activity relationship (QSAR) methods, which relate a set of predictor variables, describing the physicochemical properties of a drug–target pair, to the response variable, representing the existence or the strength of an interaction.
Current machine learning methods can be classified into two types, which are featurebased and similaritybased approaches. In featurebased methods, known drug–target interactions are represented by feature vectors generated by combining chemical descriptors of drugs with descriptors for targets [19–23]. With these feature vectors as input, standard machine learning methods such as Support Vector Machines (SVM), Naïve Bayes (NB) or Neural Networks (NN) can be used to predict the interaction of new drug–target pairs. Vina et al. [24] proposes a method taking into consideration only the sequence of the target and the chemical connectivity of the drug, but without relying on geometry optimization or drug–drug and target–target similarities. Cheng et al. [25] introduces a multitarget QSAR method that integrates chemical substructures and protein sequence descriptors to predict interactions for Gprotein coupled receptors and kinases based on two comprehensive data sets derived from the ChEMBL database. Merget et al. [26] evaluates different machine learning methods and data balancing schemes and reports that random forests yielded the best activity prediction and allowed accurate inference of compound selectivity.
In similaritybased methods [3, 27–32], similarity matrices for both the drug–drug pairs and the target–target pairs are generated. Different types of similarity metrics can be used to generate these matrices [33]; typically, chemical structure fingerprints are used to compute the similarity among drugs and a protein sequence alignment score is used for targets. One of the simplest ways of using the similarities is a Nearest Neighbor classifier [28], which predicts new interactions from the weighted (by the similarity) sum of the interaction profiles of the most similar drugs/targets. The Kernel method proposed in [27] computes a similarity for all drug–target pairs (a pairwisekernel) using the drug–drug and target–target similarities and then uses this kernel of drug–target pairs with known labels to train an SVMclassifier. The approaches presented in [28–30] represent drug–target interactions by a bipartite graph and label drug–target pairs as +1 if the edge exists or −1, otherwise. For each drug and for each target, a separate SVM (local model) is trained, which predicts interactions of that drug (target) with all targets (drugs). The similarity matrices are used as kernels for those SVMs, and the final prediction for a pair is obtained by averaging the scores for the respective drug SVM and target SVM.
All of the above machinelearning based methods for drug–target interaction prediction formulate the task as a binary classification problem, with the goal to classify a given drug–target pair as binding or nonbinding. As pointed out in [4], drawbacks of the binary problem formulation are that truenegative interactions and untested drug–target pairs are not differentiated, and that the whole interaction spectrum, including both truepositive and truenegative interactions, is not covered well. Pahikkala et al. [4] introduces the method KronRLS which predicts continuous drug–target binding affinity values. To the best of our knowledge, KronRLS is the only method in the literature which predicts continuous binding affinities, and we give a detailed introduction to KronRLS below, since we use it as baseline in our experiments. Below, we also introduce Matrix Factorization as it was used in the literature for binary drug–target interaction prediction and as it plays an important role in our proposed method.
KronRLS
Matrix factorization
The Matrix Factorization (MF) technique has been demonstrated to be effective especially for personalized recommendation tasks [34], and it has been previously applied for drug–target interaction prediction [5–7]. In MF, a matrix \(M \in R^{d \times t}\) (for the drug–target prediction task, \(M\) represents a matrix of binding affinities of \(d\) drugs and \(t\) targets) is approximated by the product of two latent factor matrices \(P \in R^{k \times d}\) and \(Q \in R^{k \times t}\).
In SimBoost, the columns of the factor matrices \(P\) and \(Q\) are utilized as parts of the feature vectors for the drugs and targets respectively and thus Matrix Factorization is used as a feature extraction step.
Methods
Problem definition
We assume input data in the format \((M,D,T)\), where \(M\) is a matrix with continuous values where \(M_{i,j}\) represents the binding affinity of drug \(i\) and target \(j\). \(D\) is a similarity matrix of drugs, and \(T\) is a similarity matrix of targets. Specifically, we define \(M_{i, \cdot }\) as the \(i\)th row of \(M\), and \(M_{ \cdot ,j}\) as the \(j\)th column of \(M\). Similarly, we define \(D_{i, \cdot }\) as the \(i\)th row of \(D\), and \(T_{ \cdot ,j}\) as the \(j\)th row of \(T\). Only a subset of the elements of \(M\) is observed, and our goal is to predict all the nonobserved values in \(M\) with the given information.
SimBoost and SimBoostQuant
Our proposed method, called SimBoost, constructs features for each drug, each target and each drug–target pair. These features represent the properties of drugs, targets and drug–target pairs, respectively. SimBoost associates a feature vector with each pair of one drug and one target. From pairs with observed binding affinities, it trains a gradient boosting machine model to learn the nonlinear relationships between the features and the binding affinities. Once the model is trained, SimBoost can make predictions of the binding affinities for unobserved drug–target pairs, based on their known features.
We also propose a version of SimBoost, called SimBoostQuant, which computes the confidence of the prediction by using quantile regression to learn a prediction interval for a given drug–target pair as a measure of the confidence of the prediction.
Feature engineering
We define three types of features to describe the properties of drugs, targets and drug–target pairs.

Number of observations in \(M\) for the object (n.obs).

The number of observations in the corresponding row/column of \(M\).


Average of all similarity scores of the object (ave.sim).

For drug \(i\), the average of \(D_{i, \cdot }\).

For target \(j\), the average of \(T_{j, \cdot }\).


Histogram of the similarity values of the object (hist.sim).

A vector of frequencies of the similarity values, where the number of bins is an input parameter.


Average of the observed values for the object in \(M\) (ave.val).

For drug \(i\), the average of \(M_{i, \cdot }\).

For target \(j\), the average of \(M_{ \cdot ,j}\).


Number of neighbours (num.nb).

The similarity values of the \(k\)nearest neighbours of the node (k.sim).

The average of the Type 1 features among the \(k\)nearest neighbours of the node (k.ave.feat), simply averaging these vectors from different objects, which results in a vector of the same length.

The average of the Type 1 features among the \(k\)nearest neighbours of the node, weighted by the similarity values (k.w.ave.feat).

Betweenness, closeness and eigenvector centrality of the node as introduced in [35] (bt, cl, ev).

PageRank score as described in [36] (pr).

Latent vectors from matrix factorization (mf).

The latent vector for the drug or the target, obtained by matrix factorization of \(M\).


Weighted scores from drug to target’s neighbours (if any) (d.t.ave).

If drug \(i\) has observed affinities with target \(j\)‘s neighbours, average the values.


Weighted scores from target to drug’s neighbours (if any) (t.d.ave).

If target \(j\) has observed affinities with drug \(i\)‘s neighbours, average the values.


Betweenness, closeness and eigenvector centrality of the node (d.t.bt, d.t.cl, d.t.ev).

PageRank score (d.t.pr).
Structure of feature vector for \((d_{i} ,t_{j} )\)
Type 1 of d _{ i }  Type 1 of t _{ j }  Type 2 of d _{ i }  Type 2 of t _{ j }  Type 3 of \((d_{i} ,t_{j} )\) 
Gradient boosting regression trees

Accuracy: the boosting algorithm is an ensemble model, which trains a sequence of “weak learners” to gradually achieve a good accuracy.

Efficiency: the training process can be parallelized, greatly reducing the training time.
In the following, we provide a brief introduction to a variant of this model, gradient boosting regression trees, which we use in our methods. The details are described in [38, 39]. In the common supervised learning scenario, the data set can be represented by a set containing \(n\) paired feature vectors and labels: \(D = \{ (x_{i} ,y_{i} )\}\) (\(D = n\)). In the context of our task, \(x_{i} \in R^{d}\) is the vector of features of the \(i\)th drug–target pair, while \(y_{i} \in R\) is its binding affinity.
A gradient boosting algorithm iteratively adds trees that optimize \(\tilde{L}^{(t)}\) for a number of userspecified iterations.
Prediction intervals
We extend gradient boosting regression trees by the concept of quantile regression to characterize the confidence of the prediction. Suppose the model can predict the quantile given the quantile parameter \(\upalpha\). To obtain the interval, we need to train the model twice to calculate the \(\upalpha\) quantile and the (\(1 \upalpha\)) quantile to get the boundary of the prediction interval. To make a prediction for binding affinity, we use the median of the interval.
The second order gradient is not applicable here, therefore we will set it to 1.
Experiments
Data
The Davis and Metz datasets are suitable for the evaluation of predictive models for drug–target interaction because data heterogeneity is not an issue. We can assume that the experimental settings for the measured drug–target pairs in each dataset were the same and the binding affinities are comparable. When working with experimental results that come from multiple sources the data might be heterogeneous: In one case the binding affinity might be measured by \(K_{i}\), in another case by \(K_{d}\) and in a third case by \(IC_{50}\). Another source of data heterogeneity are different experimental settings. An approach to integrate observations from different sources, named KIBA, and a corresponding dataset are presented in [42]. In this work the authors integrated the experimental results from multiple databases into a bioactivity matrix of 52,498 compounds and 467 targets, including 246,088 observations. The binding affinities in this matrix are given as KIBAvalues. We used this dataset to obtain a third evaluation dataset, which we call the KIBA dataset, by removing all drugs and targets with less than 10 observations from the original dataset (downloaded from the supplementary materials of [42]), resulting in a dataset of 2116 drugs and 229 targets with a density of 24%.
The statistics of the three datasets
Dataset  Number of drugs  Number of targets  Density (%) 

Davis  68  442  100 
Metz  1421  156  42.1 
KIBA  2116  229  24.4 
In the original Davis dataset a large fraction of the values is given as “>10,000K _{ d }”, meaning no binding affinity was detected in the wet lab experiment. These values were transformed to 10,000K _{ d } (5pK _{ d }) in the preprocessed dataset, which explains the high bar at value 5pK _{ d }.
As drug–drug and target–target similarity matrices for the Davis and Metz dataset we used the precomputed matrices that are provided on the website of [4]. Here, the drug–drug similarity was computed based on the 2D chemical structure of the compounds, using the structure clustering server at PubChem. This tool clusters the compounds based on the structure similarity using the single linkage algorithm [44] and allows to download a similarity matrix containing the similarity for each drug–drug pair. The target–target similarity was computed based on the protein sequences, using the normalized SmithWaterman score [3]. For the KIBA dataset we obtained the drug–drug similarity matrix through the compound clustering tool of PubChem as done by the authors of [4] for the Davis and Metz datasets. The given ChEMBL IDs of the compounds were first matched to their PubChem CIDs which were then used as input to the PubChem web interface.
The web tool allows to download a similarity matrix for the compounds as described above (similarly as for the drug–drug similarity of the Metz and David datasets). For the KIBA dataset we downloaded the protein sequences from NCBI and computed the normalized Smith Waterman similarity for each pair by aligning the sequences using the Biostrings R package.
Results
The baselines evaluated in our experiments are matrix factorization trained on continuous data (referred to as MF), and the KronRLS method trained on both continuous (referred to as Continuous KronRLS) or binarized data (referred to as Binary KronRLS). For MF, we use the implementation libmf as described in [43]. For KronRLS, we use the original code from the author of [4].
We also compare the performance of the two models we proposed. The difference lies in the loss function, the first one employs the usual squared loss (SimBoost), the second one employs the quantile regression loss (SimBoostQuant). We use the library xgboost to train the model [38].
We perform fivefold cross validation. To ensure that no target is used only for training or only for testing, we build the folds in a way such that every target has an observation in at least two folds. To test the variance of the performance scores, we repeat the cross validation ten times for each model on each dataset, and report the mean and standard deviation for each metric.
The evaluation metrics used are Root Mean Squared Error (RMSE), Area Under the Curve (AUC), Area Under the PrecisionRecall curve (AUPR) and Concordance Index (CI). The RMSE is a commonly used metric for the error in continuous prediction. The binary metrics AUC and AUPR are commonly used in the related work on drug–target interaction prediction, measuring the ranking error of the predictions. The AUPR is commonly used in these types of studies because it punishes more false positive predictions in highly unbalanced data sets [45]. The CI is a ranking metric for continuous values that was suggested by [4]. The CI over a set of paired data is the probability that the predictions for two randomly drawn drug–target pairs with different label values are predicted in the correct order.
KronRLS determines the optimal regularization parameter by an inner cross validation step, and the parameter which gives the best performance on the desired metric is selected to predict the test fold. The prediction of KronRLS might therefore depend on the used metric. Specifically, when the classification metrics AUC or AUPR are applied, KronRLS learns and predicts binary labels, meaning that the datasets are binarized according to the cutoff threshold before the training step.
Our methods in contrast only predict continuous values, and the binarization threshold is applied after the prediction step to calculate the \(AUC\) and \(AUPR\) metrics. We argue that, given two models \(A\) and \(B\), where \(A\) learns to predict continuous values and model \(B\) learns to predict binary values, and the performance of model \(A\) in terms of \(AUC\) and \(AUPR\) is as good as the performance of model \(B\), model \(A\) is advantageous because it does not need to be retrained when the threshold for the dataset is changed. For a fair comparison we also list the performance of KronRLS in terms of \(AUC\) and \(AUPR\) when continuous values were predicted and the threshold was applied after the prediction step.
Discussion
Results on the Davis data set, with the mean and standard deviation from 10 repetitions
RMSE  AUC  AUPR  CI  

MF  0.509 ± 0.010  0.876 ± 0.004  0.499 ± 0.017  0.816 ± 0.004 
Continuous KronRLS  0.608 ± 0.002  0.942 ± 0.001  0.679 ± 0.003  0.860 ± 0.001 
Binary KronRLS  –  0.931 ± 0.001  0.686 ± 0.006  – 
SimBoost  0.247 ± 0.003  0.956 ± 0.001  0.758 ± 0.005  0.884 ± 0.001 
SimBoostQuant  0.36 ± 0.001  0.942 ± 0.002  0.680 ± 0.002  0.871 ± 0.004 
Results on the Metz data set, with the mean and standard deviation from 10 repetitions
RMSE  AUC  AUPR  CI  

MF  0.303 ± 0.005  0.895 ± 0.003  0.358 ± 0.011  0.788 ± 0.001 
Continuous KronRLS  0.562 ± 0.001  0.943 ± 0.001  0.518 ± 0.003  0.789 ± 0.001 
Binary KronRLS  –  0.932 ± 0.001  0.565 ± 0.004  – 
SimBoost  0.166 ± 0.001  0.958 ± 0.001  0.629 ± 0.003  0.851 ± 0.001 
SimBoostQuant  0.249 ± 0.002  0.942 ± 0.002  0.523 ± 0.004  0.813 ± 0.020 
Results on the KIBA data set, with the mean and standard deviation from 10 repetitions
RMSE  AUC  AUPR  CI  

MF  0.382 ± 0.003  0.831 ± 0.002  0.631 ± 0.004  0.792 ± 0.001 
Continuous KronRLS  0.620 ± 0.001  0.884 ± 0.001  0.735 ± 0.001  0.792 ± 0.001 
Binary KronRLS  –  0.904 ± 0.001  0.7660 ± 0.001  – 
SimBoost  0.204 ± 0.001  0.907 ± 0.001  0.782 ± 0.001  0.847 ± 0.001 
SimBoostQuant  0.299 ± 0.001  0.875 ± 0.001  0.708 ± 0.002  0.796 ± 0.001 
We observe that SimBoost consistently outperforms all baselines on all datasets in terms of all performance metrics. Based on the standard deviation obtained from 10 repetitions, the improvement is significant (Table 4).
In particular, for the Davis dataset, SimBoost reduces the RMSE of MF by 51% and improves the AUPR of Continuous KronRLS by 12%. For the Metz dataset, SimBoost reduces the RMSE of MF by 45%, improves the AUPR of Binary KronRLS by 11% and improves the CI of MF by 8%. For the KIBA dataset, SimBoost reduces the RMSE of the MF by 47%, improves the AUPR of Binary KronRLS by 2% and improves the CI of MF by 7%.
SimBoostQuant achieves the second best performance in terms of RMSE, AUC and CI. While this model is not as good as SimBoost in terms of prediction performance, it has the advantage of quantifying the confidence of the predicted value.
The highest dashdot green line corresponds to the upper quantile, the lowest dashed red line corresponds to the lower quantile. The dotted blue line in the middle is the average of the quantiles, used as our prediction. The solid black line is the true value in the training dataset. The drugs are listed on the xaxis, sorted by the predicted value.
This is because generally the more observations, the more information has the model. For a given target, the width of the prediction interval varies a lot for different compounds, therefore among the compounds with high predicted affinities we choose those with narrower intervals.
We note that the most important features are the average affinity of the drug and the target, as well as the latent factors obtained from matrix factorization. The average affinity of a drug/target captures their typical binding behavior, which is valuable to predict the binding affinity with a specific target/drug. While SimBoost substantially outperforms matrix factorization, arguably because of its ability to discover nonlinear relationships, the latent factors learnt by MF do provide important features for SimBoost.
Conclusions
The majority of the existing cheminformatics methods for predicting drug–target interactions perform binary classification into binding and nonbinding. In this paper we proposed the novel readacross method SimBoost for the problem of predicting continuous, as opposed to binary, drug–target binding affinities. As discussed above, continuous values allow the distinction between true negatives and missing values, and provide more information about the actual strength of proteincompound binding. To the best of our knowledge, SimBoost is the first nonlinear method for continuous drug–target interaction prediction, and the first method that also computes a prediction interval as a measure of the confidence of the prediction.
In our experiments we compared SimBoost with KronRLS, the stateoftheart method for this task, on the Davis, Metz, and KIBA datasets. To the best of our knowledge, this is the first study where the KIBA dataset was used for the evaluation of drug–target interaction predictions, and we believe that it should be used in future studies as a benchmark set, because of its heterogeneous and wellbalanced nature.

We proposed the first nonlinear readacross method SimBoost for continuous drug–target binding affinity prediction. SimBoost takes informative features from the drug and target similarities and from a matrix factorization model, and trains a gradient boosting tree model.

We proposed a version of SimBoost, called SimBoostQuant, which, using the same features, predicts binding affinities as well as prediction intervals as a measure of the confidence of the prediction.

We performed extensive experiments on three datasets evaluating four performance metrics. The results demonstrate that SimBoost and SimBoostQuant consistently outperform stateoftheart methods.
It should be noted that while SimBoost is a more accurate method, SimBoostQuant provides important information on the confidence of a prediction and, thus, explicitly address the Applicability Domain challenge. In our opinion, the choice between the two methods is essentially a tradeoff between slightly more accurate versus somewhat more informative predictions.
Notes
Declarations
Authors’ contributions
ME, AC, TH and MH conceived the study. TH and MH developed the prediction methods. TH, MH and FB prepared the datasets and designed and performed the experiments. TH, MH, and ME wrote the manuscript, AC, and FB proofread it. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Availability of data and materials

http://staff.cs.utu.fi/~aatapa/data/DrugTarget/

known_drugtarget_interaction_affinities_pKi__Metz_et_al.2011.txt

drugtarget_interaction_affinities_Kd__Davis_et_al.2011.txt


http://pubs.acs.org/doi/suppl/10.1021/ci400709d

ci400709d_si_002.xlsx

The preprocessed data, code for experiments and detailed instructions are available in the following link: https://zenodo.org/record/164436.
Funding
The authors kindly acknowledge the following funding sources: NSERC Create program “Computational Methods for the Analysis of the Diversity and Dynamics of Genomes” (4339052013), AC acknowledges the NSERC Discovery grant.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Authors’ Affiliations
References
 Ding H, Takigawa I, Mamitsuka H, Zhu S (2014) Similaritybased machine learning methods for predicting drug–target interactions: a brief review. Brief Bioinform 15(5):734–747View ArticleGoogle Scholar
 Ball N, Cronin MT, Shen J, Blackburn K, Booth ED, Bouhifd M, Donley E, Egnash L, Hastings C, Juberg DR, Kleensang A (2015) Toward good readacross practice (GRAP) guidance. Altex 33(2):149–166Google Scholar
 Yamanishi Y, Araki M, Gutteridge A, Honda W, Kanehisa M (2008) Prediction of drug–target interaction networks from the integration of chemical and genomic spaces. Bioinformatics 24(13):232–240View ArticleGoogle Scholar
 Pahikkala T, Airola A, Pietila S et al (2015) Toward more realistic drugtarget interaction predictions. Brief Bioinform 16(2):325–337. doi:https://doi.org/10.1093/bib/bbu010 View ArticleGoogle Scholar
 Liu Y, Wu M, Miao C, Zhao P, Li XL (2016) Neighborhood regularized logistic matrix factorization for drug–target interaction prediction. PLoS Comput Biol 12(2):e1004760View ArticleGoogle Scholar
 Ezzat A, Zhao P, Wu M et al (2016) Drugtarget interaction prediction with graph regularized matrix factorization. IEEE/ACM Trans Comput Biol Bioinf. doi:https://doi.org/10.1109/tcbb.2016.2530062 Google Scholar
 Gonen M, Kaski S (2014) Kernelized Bayesian Matrix Factorization. IEEE Trans Pattern Anal Mach Intell 36(10):2047–2060. doi:https://doi.org/10.1109/tpami.2014.2313125 View ArticleGoogle Scholar
 Patlewicz G, Ball N, Becker RA, Booth ED, Cronin MT, Kroese D, Steup D, van Ravenzwaay B, Hartung T (2014) Food for thought: readacross approaches–misconceptions, promises and challenges ahead. Altern Anim Exp: ALTEX 31(4):387–396Google Scholar
 Meinshausen N (2006) Quantile regression forests. J Mach Learn Res 7:983–999Google Scholar
 Singh K, Shikha G (2014) NanoQSAR modeling for predicting biological activity of diverse nanomaterials. RSC Adv 4(26):13215–13230View ArticleGoogle Scholar
 Svetnik V, Wang T, Tong C, Liaw A, Sheridan R, Song Q (2015) Boosting: an ensemble learning tool for compound classification and QSAR modeling. J Chem Inf Model 45(3):786–799View ArticleGoogle Scholar
 Morris GM et al (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30(16):2785–2791View ArticleGoogle Scholar
 Cheng AC et al (2007) Structurebased maximal affinity model predicts smallmolecule druggability. Nat Biotechnol 25(1):71–75View ArticleGoogle Scholar
 Rarey M et al (1996) A fast flexible docking method using an incremental construction algorithm. J Mol Biol 261(3):470–489View ArticleGoogle Scholar
 Campillos M et al (2008) Drug target identification using sideeffect similarity. Science 321(5886):263–266View ArticleGoogle Scholar
 Kinnings SL et al (2009) Drug discovery using chemical systems biology: repositioning the safe medicine Comtan to treat multidrug and extensively drug resistant tuberculosis. PLoS Comput Biol 5(7):e1000423View ArticleGoogle Scholar
 Li YY, An J, Jones SJM (2011) A computational approach to finding novel targets for existing drugs. PLoS Comput Biol 7(9):e1002139View ArticleGoogle Scholar
 Wang K et al (2013) Prediction of drug–target interactions for drug repositioning only based on genomic expression similarity. PLoS Comput Biol 9(11):e1003315View ArticleGoogle Scholar
 Yabuuchi H et al (2011) Analysis of multiple compound–protein interactions reveals novel bioactive molecules. Mol Syst Biol 7(1):472View ArticleGoogle Scholar
 Nagamine N, Sakakibara Y (2007) Statistical prediction of protein–chemical interactions based on chemical structure and mass spectrometry data. Bioinformatics 23(15):2004–2012View ArticleGoogle Scholar
 Nagamine N et al (2009) Integrating statistical predictions and experimental verifications for enhancing protein–chemical interaction predictions in virtual screening. PLoS Comput Biol 5(6):e1000397View ArticleGoogle Scholar
 Schürer SC, Muskal SM (2013) Kinomewide activity modeling from diverse public highquality data sets. J Chem Inf Model 53(1):27–38View ArticleGoogle Scholar
 Manallack DT et al (2002) Selecting screening candidates for kinase and G proteincoupled receptor targets using neural networks. J Chem Inf Comput Sci 42(5):1256–1262View ArticleGoogle Scholar
 Vina D et al (2009) Alignmentfree prediction of a drug–target complex network based on parameters of drug connectivity and protein sequence of receptors. Mol Pharm 6(3):825–835View ArticleGoogle Scholar
 Cheng F et al (2012) Prediction of chemical–protein interactions: multitargetQSAR versus computational chemogenomic methods. Mol BioSyst 8(9):2373–2384View ArticleGoogle Scholar
 Merget B, Turk S, Eid S et al (2017) Profiling prediction of kinase inhibitors: toward the virtual assay. J Med Chem 60(1):474–485. doi:https://doi.org/10.1021/acs.jmedchem.6b01611 View ArticleGoogle Scholar
 Jacob L, Vert JP (2008) Protein–ligand interaction prediction: an improved chemogenomics approach. Bioinformatics 24(19):2149–2156View ArticleGoogle Scholar
 Bleakley K, Yamanishi Y (2009) Supervised prediction of drug–target interactions using bipartite local models. Bioinformatics 25(18):2397–2403View ArticleGoogle Scholar
 Bleakley K, Biau G, Vert JP (2007) Supervised reconstruction of biological networks with local models. Bioinformatics 23(13):i57–i65View ArticleGoogle Scholar
 Mordelet F, Vert JP (2008) SIRENE: supervised inference of regulatory networks. Bioinformatics 24(16):i76–i82View ArticleGoogle Scholar
 Xia Z, Wu LY, Zhou X, Wong ST (2010) Semisupervised drugprotein interaction prediction from heterogeneous biological spaces. BMC Syst Biol. 4(Suppl 2):S6. doi:https://doi.org/10.1186/175205094s2s6 View ArticleGoogle Scholar
 van Laarhoven T, Nabuurs SB, Marchiori E (2011) Gaussian interaction profile kernels for predicting drug–target interaction. Bioinformatics 27(21):3036–3043View ArticleGoogle Scholar
 Öztürk H, Ozkirimli E, Özgür A (2016) A comparative study of SMILESbased compound similarity functions for drug–target interaction prediction. BMC Bioinformatics 17(1):128View ArticleGoogle Scholar
 Koren Y, Bell R, Volinsky C (2009) Matrix factorization techniques for recommender systems. Computer 42(8):30–37View ArticleGoogle Scholar
 Newman M (2010) Networks: an introduction. Oxford University Press, OxfordView ArticleGoogle Scholar
 Page L et al (1999) The PageRank citation ranking: bringing order to the web. Stanford InfoLab, StanfordGoogle Scholar
 Friedman JH (2001) Greedy function approximation: a gradient boosting machine. Ann Stat 1:1189–1232View ArticleGoogle Scholar
 Chen T, He T (2015) Higgs boson discovery with boosted trees. In: Cowan et al (eds) JMLR: workshop and conference proceedings 2015, vol 42, pp 69–80Google Scholar
 Chen T, Guestrin C (2016) Xgboost: a scalable tree boosting system. arXiv preprint arXiv:1603.02754
 Metz JT, Johnson EF, Soni NB, Merta PJ, Kifle L, Hajduk PJ (2011) Navigating the kinome. Nat Chem Biol 7(4):200–202View ArticleGoogle Scholar
 Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol 29(11):1046–1051View ArticleGoogle Scholar
 Tang J, Szwajda A, Shakyawar S, Xu T, Hintsanen P, Wennerberg K, Aittokallio T (2014) Making sense of largescale kinase inhibitor bioactivity data sets: a comparative and integrative analysis. J Chem Inf Model 54(3):735–743View ArticleGoogle Scholar
 Chin WS, Yuan BW, Yang MY, Zhuang Y, Juan YC, Lin CJ (2016) LIBMF: a library for parallel matrix factorization in sharedmemory systems. J Mach Learn Res 17(86):1–5Google Scholar
 Olson CF (1995) Parallel algorithms for hierarchical clustering. Parallel Comput 21(8):1313–1325View ArticleGoogle Scholar
 Yang F, Xu J, Zeng J (2014) Drug–target interaction prediction by integrating chemical, genomic, functional and pharmacological data. In: Pacific symposium on biocomputing. NIH Public AccessGoogle Scholar