Chemogenomic Analysis of G-Protein Coupled Receptors and Their Ligands Deciphers Locks and Keys Governing Diverse Aspects of Signalling

Understanding the molecular mechanism of signalling in the important super-family of G-protein-coupled receptors (GPCRs) is causally related to questions of how and where these receptors can be activated or inhibited. In this context, it is of great interest to unravel the common molecular features of GPCRs as well as those related to an active or inactive state or to subtype specific G-protein coupling. In our underlying chemogenomics study, we analyse for the first time the statistical link between the properties of G-protein-coupled receptors and GPCR ligands. The technique of mutual information (MI) is able to reveal statistical inter-dependence between variations in amino acid residues on the one hand and variations in ligand molecular descriptors on the other. Although this MI analysis uses novel information that differs from the results of known site-directed mutagenesis studies or published GPCR crystal structures, the method is capable of identifying the well-known common ligand binding region of GPCRs between the upper part of the seven transmembrane helices and the second extracellular loop. The analysis shows amino acid positions that are sensitive to either stimulating (agonistic) or inhibitory (antagonistic) ligand effects or both. It appears that amino acid positions for antagonistic and agonistic effects are both concentrated around the extracellular region, but selective agonistic effects are cumulated between transmembrane helices (TMHs) 2, 3, and ECL2, while selective residues for antagonistic effects are located at the top of helices 5 and 6. Above all, the MI analysis provides detailed indications about amino acids located in the transmembrane region of these receptors that determine G-protein signalling pathway preferences

Modeling Physico-Chemical ADMET Endpoints With Multitask Graph Convolutional Networks

Simple physico-chemical properties like logD, solubility or serum albumin binding have a direct impact on the likelihood of success of compounds in clinical trials. Here, we collected all the Bayer in house data related to these properties and applied machine learning techniques to predict them for new compounds. We report that, for the endpoints studied here, a multitask graph convolutional network appears a highly competitive choice. The new model shows increased predictive performance on all endpoints compared to previous modeling methods.<br /

Large-scale evaluation of k-fold cross-validation ensembles for uncertainty estimation

Abstract It is insightful to report an estimator that describes how certain a model is in a prediction, additionally to the prediction alone. For regression tasks, most approaches implement a variation of the ensemble method, apart from few exceptions. Instead of a single estimator, a group of estimators yields several predictions for an input. The uncertainty can then be quantified by measuring the disagreement between the predictions, for example by the standard deviation. In theory, ensembles should not only provide uncertainties, they also boost the predictive performance by reducing errors arising from variance. Despite the development of novel methods, they are still considered the “golden-standard” to quantify the uncertainty of regression models. Subsampling-based methods to obtain ensembles can be applied to all models, regardless whether they are related to deep learning or traditional machine learning. However, little attention has been given to the question whether the ensemble method is applicable to virtually all scenarios occurring in the field of cheminformatics. In a widespread and diversified attempt, ensembles are evaluated for 32 datasets of different sizes and modeling difficulty, ranging from physicochemical properties to biological activities. For increasing ensemble sizes with up to 200 members, the predictive performance as well as the applicability as uncertainty estimator are shown for all combinations of five modeling techniques and four molecular featurizations. Useful recommendations were derived for practitioners regarding the success and minimum size of ensembles, depending on whether predictive performance or uncertainty quantification is of more importance for the task at hand

Efficiency of different measures for defining the applicability domain of classification models

Abstract The goal of defining an applicability domain for a predictive classification model is to identify the region in chemical space where the model’s predictions are reliable. The boundary of the applicability domain is defined with the help of a measure that shall reflect the reliability of an individual prediction. Here, the available measures are differentiated into those that flag unusual objects and which are independent of the original classifier and those that use information of the trained classifier. The former set of techniques is referred to as novelty detection while the latter is designated as confidence estimation. A review of the available confidence estimators shows that most of these measures estimate the probability of class membership of the predicted objects which is inversely related to the error probability. Thus, class probability estimates are natural candidates for defining the applicability domain but were not comprehensively included in previous benchmark studies. The focus of the present study is to find the best measure for defining the applicability domain for a given binary classification technique and to determine the performance of novelty detection versus confidence estimation. Six different binary classification techniques in combination with ten data sets were studied to benchmark the various measures. The area under the receiver operating characteristic curve (AUC ROC) was employed as main benchmark criterion. It is shown that class probability estimates constantly perform best to differentiate between reliable and unreliable predictions. Previously proposed alternatives to class probability estimates do not perform better than the latter and are inferior in most cases. Interestingly, the impact of defining an applicability domain depends on the observed area under the receiver operator characteristic curve. That means that it depends on the level of difficulty of the classification problem (expressed as AUC ROC) and will be largest for intermediately difficult problems (range AUC ROC 0.7–0.9). In the ranking of classifiers, classification random forests performed best on average. Hence, classification random forests in combination with the respective class probability estimate are a good starting point for predictive binary chemoinformatic classifiers with applicability domain. Graphical abstract

Estimating the Domain of Applicability for Machine Learning QSAR RModels: A Study on Aqueous Solubility of Drug Discovery Molecules

We investigate the use of different Machine Learning methods to construct models for aqueous solubility. Models are based on about 4000 compounds, including an in-house set of 632 drug discovery molecules of Bayer Schering Pharma. For each method, we also consider an appropriate method to obtain error bars, in order to estimate the domain of applicability for each model. Here, we investigate error bars from a Bayesian model (Gaussian Process), an ensemble based approach (Random Forest), and approaches based on the Mahalanobis distance to training data (for Support Vector Machine and Ridge Regression models). We evaluate all approaches in terms of their prediction accuracy (in cross-validation, and on an external validation set of 536 molecules) and in how far the individual error bars can faithfully represent the actual prediction error.

Machine Learning Models for Lipophilicity and their Domain of Applicability

Unfavorable lipophilicity and water solubility cause many drug failures, therefore these properties have to be taken into account early on in lead discovery. Commercial tools for predicting lipophilicity usually have been trained on small and neutral molecules, and are thus often unable to accurately predict in-house data. Using a modern Bayesian machine learning algorithm—a Gaussian Process model—this study constructs a log D7 model based on 14556 drug discovery compounds of Bayer Schering Pharma. Performance is compared with support vector machines, decision trees, ridge regression and four commercial tools. In a blind test on 7013 new measurements from the last months (including compounds from new projects) 81 % were predicted correctly within one log unit, compared to only 44 % achieved by commercial software. Additional evaluations using public data are presented. We consider error bars for each method (model based error bars, ensemble based, and distance based approaches), and investigate how well they quantify the domain of applicability of each model

Comprehensive and Automated Linear Interaction Energy Based Binding-Affinity Prediction for Multifarious Cytochrome P450 Aromatase Inhibitors

Cytochrome P450 aromatase (CYP19A1) plays a key role in the development of estrogen dependent breast cancer, and aromatase inhibitors have been at the front line of treatment for the past three decades. The development of potent, selective and safer inhibitors is ongoing with in silico screening methods playing a more prominent role in the search for promising lead compounds in bioactivity-relevant chemical space. Here we present a set of comprehensive binding affinity prediction models for CYP19A1 using our automated Linear Interaction Energy (LIE) based workflow on a set of 132 putative and structurally diverse aromatase inhibitors obtained from a typical industrial screening study. We extended the workflow with machine learning methods to automatically cluster training and test compounds in order to maximize the number of explained compounds in one or more predictive LIE models. The method uses protein-ligand interaction profiles obtained from Molecular Dynamics (MD) trajectories to help model search and define the applicability domain of the resolved models. Our method was successful in accounting for 86% of the data set in 3 robust models that show high correlation between calculated and observed values for ligand-binding free energies (RMSE < 2.5 kJ mol(-1)), with good cross-validation statistics

Accurate Solubility Prediction with Error Bars for Electrolytes: A Machine Learning Approach

Accurate in-silico models for predicting aqueous solubility are needed in drug design and discovery, and many other areas of chemical research. We present a statistical modelling of aqueous solubility based on measured data, using a Gaussian Process nonlinear regression model (GPsol). We compare our results with those of 14 scientific studies and 6 commercial tools. This shows that the developed model achieves much higher accuracy than available commercial tools for the prediction of solubility of electrolytes. On top of the high accuracy, the proposed machine learning model also provides error bars for each individual prediction