General Strategies.- Regression Models.- Classification Models.- Other Considerations.- Appendix.- References.- Indices.

Applied Predictive Modeling

The Tox21 Data Challenge has been the largest effort of the scientific community to compare computational methods for toxicity prediction. This challenge comprised 12,000 environmental chemicals and drugs which were measured for 12 different toxic effects by specifically designed assays. We participated in this challenge to assess the performance of Deep Learning in computational toxicity prediction. Deep Learning has already revolutionized image processing, speech recognition, and language understanding but has not yet been applied to computational toxicity. Deep Learning is founded on novel algorithms and architectures for artificial neural networks together with the recent availability of very fast computers and massive datasets. It discovers multiple levels of distributed representations of the input, with higher levels representing more abstract concepts. We hypothesized that the construction of a hierarchy of chemical features gives Deep Learning the edge over other toxicity prediction methods. Furthermore, Deep Learning naturally enables multi-task learning, that is, learning of all toxic effects in one neural network and thereby learning of highly informative chemical features. In order to utilize Deep Learning for toxicity prediction, we have developed the DeepTox pipeline. First, DeepTox normalizes the chemical representations of the compounds. Then it computes a large number of chemical descriptors that are used as input to machine learning methods. In its next step, DeepTox trains models, evaluates them, and combines the best of them to ensembles. Finally, DeepTox predicts the toxicity of new compounds. In the Tox21 Data Challenge, DeepTox had the highest performance of all computational methods winning the grand challenge, the nuclear receptor panel, the stress response panel, and six single assays (teams ``Bioinf@JKU''). We found that Deep Learning excelled in toxicity prediction and outperformed many other computational approaches like naive Bayes, support vector machines, and random forests.

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DeepTox: Toxicity Prediction using Deep Learning

In recent years the use of graph based representation has gained popularity in pattern recognition and machine learning. As a matter of fact, object representation by means of graphs has a number of advantages over feature vectors. Therefore, various algorithms for graph based machine learning have been proposed in the literature. However, in contrast with the emerging interest in graph based representation, a lack of standardized graph data sets for benchmarking can be observed. Common practice is that researchers use their own data sets, and this behavior cumbers the objective evaluation of the proposed methods. In order to make the different approaches in graph based machine learning better comparable, the present paper aims at introducing a repository of graph data sets and corresponding benchmarks, covering a wide spectrum of different applications.

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IAM Graph Database Repository for Graph Based Pattern Recognition and Machine Learning

Kernel-based techniques (such as support vector machines, Bayes point machines, kernel principal component analysis, and Gaussian processes) represent a major development in machine learning algorithms. Support vector machines (SVM) are a group of supervised learning methods that can be applied to classification or regression. In a short period of time, SVM found numerous applications in chemistry, such as in drug design (discriminating between ligands and nonligands, inhibitors and noninhibitors, etc.), quantitative structure-activity relationships (QSAR, where SVM regression is used to predict various physical, chemical, or biological properties), chemometrics (optimization of chromatographic separation or compound concentration prediction from spectral data as examples), sensors (for qualitative and quantitative prediction from sensor data), chemical engineering (fault detection and modeling of industrial processes), and text mining (automatic recognition of scientific information). Support vector machines represent an extension to nonlinear models of the generalized portrait algorithm developed by Vapnik and Lerner. The SVM algorithm is based on the statistical learning theory and the Vapnik–Chervonenkis

Applications of Support Vector Machines in Chemistry

Motivation: Predicting interactions between small molecules and proteins is a crucial step to decipher many biological processes, and plays a critical role in drug discovery. When no detailed 3D structure of the protein target is available, ligand-based virtual screening allows the construction of predictive models by learning to discriminate known ligands from non-ligands. However, the accuracy of ligand-based models quickly degrades when the number of known ligands decreases, and in particular the approach is not applicable for orphan receptors with no known ligand.

Results: We propose a systematic method to predict ligand–protein interactions, even for targets with no known 3D structure and few or no known ligands. Following the recent chemogenomics trend, we adopt a cross-target view and attempt to screen the chemical space against whole families of proteins simultaneously. The lack of known ligand for a given target can then be compensated by the availability of known ligands for similar targets. We test this strategy on three important classes of drug targets, namely enzymes, G-protein-coupled receptors (GPCR) and ion channels, and report dramatic improvements in prediction accuracy over classical ligand-based virtual screening, in particular for targets with few or no known ligands.

Availability: All data and algorithms are available as Supplementary Material.

Contact: laurent.jacob@ensmp.fr

Supplementary information:Supplementary data are available at Bioinformatics online.

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Protein-ligand interaction prediction

The support vector machine algorithm together with graph kernel functions has recently been introduced to model structure-activity relationships (SAR) of molecules from their 2D structure, without the need for explicit molecular descriptor computation. We propose two extensions to this approach with the double goal to reduce the computational burden associated with the model and to enhance its predictive accuracy: description of the molecules by a Morgan index process and definition of a second-order Markov model for random walks on 2D structures. Experiments on two mutagenicity data sets validate the proposed extensions, making this approach a possible complementary alternative to other modeling strategies.

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Jean-Luc Perret

Papers

Graph Kernels for Molecular Structure−Activity Relationship Analysis with Support Vector Machines