Multi-Task Neural Networks and Molecular Fingerprints to Enhance Compound Identification from LC-MS/MS Data.

Mass spectrometry (MS) is widely used for the identification of chemical compounds by matching the experimentally acquired mass spectrum against a database of reference spectra. However, this approach suffers from a limited coverage of the existing databases causing a failure in the identification of a compound not present in the database. Among the computational approaches for mining metabolite structures based on MS data, one option is to predict molecular fingerprints from the mass spectra by means of chemometric strategies and then use them to screen compound libraries. This can be carried out by calibrating multi-task artificial neural networks from large datasets of mass spectra, used as inputs, and molecular fingerprints as outputs. In this study, we prepared a large LC-MS/MS dataset from an on-line open repository. These data were used to train and evaluate deep-learning-based approaches to predict molecular fingerprints and retrieve the structure of unknown compounds from their LC-MS/MS spectra. Effects of data sparseness and the impact of different strategies of data curing and dimensionality reduction on the output accuracy have been evaluated. Moreover, extensive diagnostics have been carried out to evaluate modelling advantages and drawbacks as a function of the explored chemical space.

Parsimonious Optimization of Multitask Neural Network Hyperparameters.

Neural networks are rapidly gaining popularity in chemical modeling and Quantitative Structure-Activity Relationship (QSAR) thanks to their ability to handle multitask problems. However, outcomes of neural networks depend on the tuning of several hyperparameters, whose small variations can often strongly affect their performance. Hence, optimization is a fundamental step in training neural networks although, in many cases, it can be very expensive from a computational point of view. In this study, we compared four of the most widely used approaches for tuning hyperparameters, namely, grid search, random search, tree-structured Parzen estimator, and genetic algorithms on three multitask QSAR datasets. We mainly focused on parsimonious optimization and thus not only on the performance of neural networks, but also the computational time that was taken into account. Furthermore, since the optimization approaches do not directly provide information about the influence of hyperparameters, we applied experimental design strategies to determine their effects on the neural network performance. We found that genetic algorithms, tree-structured Parzen estimator, and random search require on average 0.08% of the hours required by grid search; in addition, tree-structured Parzen estimator and genetic algorithms provide better results than random search.

NURA: A curated dataset of nuclear receptor modulators.

Nuclear receptors (NRs) are key regulators of human health and constitute a relevant target for medicinal chemistry applications as well as for toxicological risk assessment. Several open databases dedicated to small molecules that modulate NRs exist; however, depending on their final aim (i.e., adverse effect assessment or drug design), these databases contain a different amount and type of annotated molecules, along with a different distribution of experimental bioactivity values. Stemming from these considerations, in this work we aim to provide a unified dataset, NURA (NUclear Receptor Activity) dataset, collecting curated information on small molecules that modulate NRs, to be intended for both pharmacological and toxicological applications. NURA contains bioactivity annotations for 15,247 molecules and 11 selected NRs, and it was obtained by integrating and curating data from toxicological and pharmacological databases (i.e., Tox21, ChEMBL, NR-DBIND and BindingDB). Our results show that NURA dataset is a useful tool to bridge the gap between toxicology- and medicinal-chemistry-related databases, as it is enriched in terms of number of molecules, structural diversity and covered atomic scaffolds compared to the single sources. To the best of our knowledge, NURA dataset is the most exhaustive collection of small molecules annotated for their modulation of the chosen nuclear receptors. NURA dataset is intended to support decision-making in pharmacology and toxicology, as well as to contribute to data-driven applications, such as machine learning. The dataset and the data curation pipeline can be downloaded free of charge on Zenodo at the following DOI: https://doi.org/10.5281/zenodo.3991561.

Consensus versus Individual QSARs in Classification: Comparison on a Large-Scale Case Study.

Consensus strategies have been widely applied in many different scientific fields, based on the assumption that the fusion of several sources of information increases the outcome reliability. Despite the widespread application of consensus approaches, their advantages in quantitative structure-activity relationship (QSAR) modeling have not been thoroughly evaluated, mainly due to the lack of appropriate large-scale data sets. In this study, we evaluated the advantages and drawbacks of consensus approaches compared to single classification QSAR models. To this end, we used a data set of three properties (androgen receptor binding, agonism, and antagonism) for approximately 4000 molecules with predictions performed by more than 20 QSAR models, made available in a large-scale collaborative project. The individual QSAR models were compared with two consensus approaches, majority voting and the Bayes consensus with discrete probability distributions, in both protective and nonprotective forms. Consensus strategies proved to be more accurate and to better cover the analyzed chemical space than individual QSARs on average, thus motivating their widespread application for property prediction. Scripts and data to reproduce the results of this study are available for download.

Structural alerts for the identification of bioaccumulative compounds.

Legislators have included bioaccumulation in the evaluation of chemicals in the framework of the European Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) regulation. REACH requires information on the bioconcentration factor (BCF), which is a parameter for assessing bioaccumulation and encourages the use of a weight-of-evidence approach, including predictions from quantitative structure-activity relationships (QSARs). This study presents a novel approach, based on structural alerts, to be used as a decision-support system for the identification of substances with bioaccumulation potential. In a regulatory framework, these alerts can be integrated with other sources of information, such as experimental and in silico data, to reduce the uncertainty of the assessment, thereby supporting a weight-of-evidence approach. Moreover, the identified alerts have a direct connection with relevant structural features, thus fostering the applicability and interpretability of the approach. The structural alerts were identified on 779 chemicals annotated for their fish BCF, and the approach was then validated on 278 external molecules. The developed decision-support system allowed identification of 77% of bioaccumulative chemicals and was competitive with more complex QSAR models used in regulatory assessments. The approach is implemented in an easy-to-use workflow, provided free of charge. Integr Environ Assess Manag 2019;15:19-28. © 2018 SETAC.

QSAR modeling of Daphnia magna and fish toxicities of biocides using 2D descriptors.

In the recent years, ecotoxicological hazard potential of biocidal products has been receiving increasing attention in the industries and regulatory agencies. Biocides/pesticides are currently one of the most studied groups of compounds, and their registration cannot be done without the empirical toxicity information. In view of limited experimental data available for these compounds, we have developed Quantitative Structure-Activity Relationship (QSAR) models for the toxicity of biocides to fish and Daphnia magna following principles of QSAR modeling recommended by the OECD (Organization for Economic Cooperation and Development). The models were developed using simple and interpretable 2D descriptors and validated using stringent tests. Both models showed encouraging statistical quality in terms of determination coefficient R2 (0.800 and 0.648), cross-validated leave-one-out Q2 (0.760 and 0.602) and predictive R2pred or Q2ext (0.875 and 0.817) for fish (nTraining = 66, nTest = 22) and Daphnia magna (nTraining = 100, nTest = 33) toxicity datasets, respectively. These models should be applicable for data gap filling in case of new or untested biocidal compounds falling within the applicability domain of the models. In general, the models indicate that the toxicity increases with lipophilicity and decreases with polarity, branching and unsaturation. We have also developed interspecies toxicity models for biocides using the daphnia and fish toxicity data and used the models for data gap filling.