A renaissance of neural networks in drug discovery

© 2016 Informa UK Limited, trading as Taylor & Francis Group.Introduction: Neural networks are becoming a very popular method for solving machine learning and artificial intelligence problems. The variety of neural network types and their application to drug discovery requires expert knowledge to choose the most appropriate approach. Areas covered: In this review, the authors discuss traditional and newly emerging neural network approaches to drug discovery. Their focus is on backpropagation neural networks and their variants, self-organizing maps and associated methods, and a relatively new technique, deep learning. The most important technical issues are discussed including overfitting and its prevention through regularization, ensemble and multitask modeling, model interpretation, and estimation of applicability domain. Different aspects of using neural networks in drug discovery are considered: building structure-activity models with respect to various targets; predicting drug selectivity, toxicity profiles, ADMET and physicochemical properties; characteristics of drug-delivery systems and virtual screening. Expert opinion: Neural networks continue to grow in importance for drug discovery. Recent developments in deep learning suggests further improvements may be gained in the analysis of large chemical data sets. It’s anticipated that neural networks will be more widely used in drug discovery in the future, and applied in non-traditional areas such as drug delivery systems, biologically compatible materials, and regenerative medicine

Public (Q)SAR Services, Integrated Modeling Environments, and Model Repositories on the Web: State of the Art and Perspectives for Future Development

© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, WeinheimThousands of (Quantitative) Structure-Activity Relationships (Q)SAR models have been described in peer-reviewed publications; however, this way of sharing seldom makes models available for the use by the research community outside of the developer's laboratory. Conversely, on-line models allow broad dissemination and application representing the most effective way of sharing the scientific knowledge. Approaches for sharing and providing on-line access to models range from web services created by individual users and laboratories to integrated modeling environments and model repositories. This emerging transition from the descriptive and informative, but “static”, and for the most part, non-executable print format to interactive, transparent and functional delivery of “living” models is expected to have a transformative effect on modern experimental research in areas of scientific and regulatory use of (Q)SAR models

QSAR models and scaffold-based analysis of non-nucleoside HIV RT inhibitors

© 2015 Elsevier B.V. A selection of 289 pyrimidine derivatives with anti-HIV RT activities as non-nucleoside HIV RT inhibitors (NNRTI) were studied. The associative neural network (ASNN) method was applied to develop a quantitative structure-activity relationship (QSAR) for anti-HIV RT activity. The calculated models were validated using the bagging approach. A consensus model with R2=0.87 and RMSE=0.5 was obtained from 10 individual models. Scaffold analysis and molecular docking of the compounds used in the QSAR model identified a potential chemical scaffold. The results showed that scaffold-based analysis of the QSAR model could be helpful in identifying potent scaffolds for further exploration than analyzing the overall model. Matched molecular pair analysis (MMPA) was applied in the QSAR model to characterize molecular transformations causing a significant change in the anti-HIV activity. The linear QSAR model was calculated to explore the structural features important for NNRTI activity. The results revealed that the activity of NNRT inhibitors is strongly dependent on their aromaticity and structural flexibility. The scaffold-based analysis of QSAR models with molecular docking and MMPA was found to be helpful in characterizing potential scaffolds for anti-HIV RT derivatives. The outcome of this study provides a deeper insight into the computer-aided scaffold-based design of novel molecules with HIV RT activities. It was also clearly shown that the consensus model's failure to correctly predict new chemical series could be due to the limitation of its applicability domain (AD). Redevelopment of models using new measurements can dramatically increase their AD and performance

Critical assessment of QSAR models of environmental toxicity against Tetrahymena pyriformis: focusing on applicability domain and overfitting by variable selection

The estimation of the accuracy of predictions is a critical problem in QSAR modeling. The "distance to model" can be defined as a metric that defines the similarity between the training set molecules and the test set compound for the given property in the context of a specific model. It could be expressed in many different ways, e.g., using Tanimoto coefficient, leverage, correlation in space of models, etc. In this paper we have used mixtures of Gaussian distributions as well as statistical tests to evaluate six types of distances to models with respect to their ability to discriminate compounds with small and large prediction errors. The analysis was performed for twelve QSAR models of aqueous toxicity against T. pyriformis obtained with different machine-learning methods and various types of descriptors. The distances to model based on standard deviation of predicted toxicity calculated from the ensemble of models afforded the best results. This distance also successfully discriminated molecules with low and large prediction errors for a mechanism-based model developed using log P and the Maximum Acceptor Superdelocalizability descriptors. Thus, the distance to model metric could also be used to augment mechanistic QSAR models by estimating their prediction errors. Moreover, the accuracy of prediction is mainly determined by the training set data distribution in the chemistry and activity spaces but not by QSAR approaches used to develop the models. We have shown that incorrect validation of a model may result in the wrong estimation of its performance and suggested how this problem could be circumvented. The toxicity of 3182 and 48774 molecules from the EPA High Production Volume (HPV) Challenge Program and EINECS (European chemical Substances Information System), respectively, was predicted, and the accuracy of prediction was estimated. The developed models are available online at http://www.qspr.org site

A middle time recognition of epileptic seizures from geometrical patterns of EEG data

An approach for middle- time recognition of epileptic seizures from EEG data is proposed. The method considers sharp changes in the recorded data using geometrical patterns of the signal in phase-space. The approach was developed using experimental clinical EEG data recorded from ten patients and reliably predicted epileptic seizures in the ten-minute interval before the seizure onsets. An estimation of sensitivity and specificity of the proposed method is also provided.Запропоновано підхід до передбачення епілептичних припадків з ЕЕГ даних на середньотермінових інтервалах. Метод вивчає різкі зміни в отриманих даних використовуючи геометричну картину сигналу в фазовому просторі. Підхід развинено на основі використання реальних клінічних ЕЕГ даних, що записані у десяти пацієнтів, і показано передбачення епілептичних припадків за час до десяти хвилин перед припадком. Запропоновані також оцінки чутливості та особливостей запропонованого підходу.Предложен подход для предсказания эпилептических припадков из ЭЭГ данных на средневременных интервалах. Метод изучает резкие изменения в полученных данных используя геометрическую картину сигнала в фазовом пространстве. Подход развит на основе использования реальных клинических ЭЭГ данных записанных у десяти пациентов и показал предсказание эпилептических припадков за время до десяти минут перед припадком. Предложены также оценки чувствительности и особенностей предложенного подхода

How accurately can we predict the melting points of drug-like compounds?

© 2014 American Chemical Society. This article contributes a highly accurate model for predicting the melting points (MPs) of medicinal chemistry compounds. The model was developed using the largest published data set, comprising more than 47k compounds. The distributions of MPs in drug-like and drug lead sets showed that >90% of molecules melt within [50,250]°C. The final model calculated an RMSE of less than 33 °C for molecules from this temperature interval, which is the most important for medicinal chemistry users. This performance was achieved using a consensus model that performed calculations to a significantly higher accuracy than the individual models. We found that compounds with reactive and unstable groups were overrepresented among outlying compounds. These compounds could decompose during storage or measurement, thus introducing experimental errors. While filtering the data by removing outliers generally increased the accuracy of individual models, it did not significantly affect the results of the consensus models. Three analyzed distance to models did not allow us to flag molecules, which had MP values fell outside the applicability domain of the model. We believe that this negative result and the public availability of data from this article will encourage future studies to develop better approaches to define the applicability domain of models. The final model, MP data, and identified reactive groups are available online at http://ochem.eu/article/55638

Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von hippel-lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities

E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities

QSAR-derived affinity fingerprints (part 1): fingerprint construction and modeling performance for similarity searching, bioactivity classification and scaffold hopping

Funder: FP7 People: Marie-Curie Actions; doi: http://dx.doi.org/10.13039/100011264; Grant(s): 238701, 238701Abstract: An affinity fingerprint is the vector consisting of compound’s affinity or potency against the reference panel of protein targets. Here, we present the QAFFP fingerprint, 440 elements long in silico QSAR-based affinity fingerprint, components of which are predicted by Random Forest regression models trained on bioactivity data from the ChEMBL database. Both real-valued (rv-QAFFP) and binary (b-QAFFP) versions of the QAFFP fingerprint were implemented and their performance in similarity searching, biological activity classification and scaffold hopping was assessed and compared to that of the 1024 bits long Morgan2 fingerprint (the RDKit implementation of the ECFP4 fingerprint). In both similarity searching and biological activity classification, the QAFFP fingerprint yields retrieval rates, measured by AUC (~ 0.65 and ~ 0.70 for similarity searching depending on data sets, and ~ 0.85 for classification) and EF5 (~ 4.67 and ~ 5.82 for similarity searching depending on data sets, and ~ 2.10 for classification), comparable to that of the Morgan2 fingerprint (similarity searching AUC of ~ 0.57 and ~ 0.66, and EF5 of ~ 4.09 and ~ 6.41, depending on data sets, classification AUC of ~ 0.87, and EF5 of ~ 2.16). However, the QAFFP fingerprint outperforms the Morgan2 fingerprint in scaffold hopping as it is able to retrieve 1146 out of existing 1749 scaffolds, while the Morgan2 fingerprint reveals only 864 scaffolds

QSAR-derived affinity fingerprints (part 1): fingerprint construction and modeling performance for similarity searching, bioactivity classification and scaffold hopping

Funder: FP7 People: Marie-Curie Actions; doi: http://dx.doi.org/10.13039/100011264; Grant(s): 238701, 238701Abstract: An affinity fingerprint is the vector consisting of compound’s affinity or potency against the reference panel of protein targets. Here, we present the QAFFP fingerprint, 440 elements long in silico QSAR-based affinity fingerprint, components of which are predicted by Random Forest regression models trained on bioactivity data from the ChEMBL database. Both real-valued (rv-QAFFP) and binary (b-QAFFP) versions of the QAFFP fingerprint were implemented and their performance in similarity searching, biological activity classification and scaffold hopping was assessed and compared to that of the 1024 bits long Morgan2 fingerprint (the RDKit implementation of the ECFP4 fingerprint). In both similarity searching and biological activity classification, the QAFFP fingerprint yields retrieval rates, measured by AUC (~ 0.65 and ~ 0.70 for similarity searching depending on data sets, and ~ 0.85 for classification) and EF5 (~ 4.67 and ~ 5.82 for similarity searching depending on data sets, and ~ 2.10 for classification), comparable to that of the Morgan2 fingerprint (similarity searching AUC of ~ 0.57 and ~ 0.66, and EF5 of ~ 4.09 and ~ 6.41, depending on data sets, classification AUC of ~ 0.87, and EF5 of ~ 2.16). However, the QAFFP fingerprint outperforms the Morgan2 fingerprint in scaffold hopping as it is able to retrieve 1146 out of existing 1749 scaffolds, while the Morgan2 fingerprint reveals only 864 scaffolds