Dataset Information

ADMET evaluation in drug discovery. 20. Prediction of breast cancer resistance protein inhibition through machine learning.

ABSTRACT: Breast cancer resistance protein (BCRP/ABCG2), an ATP-binding cassette (ABC) efflux transporter, plays a critical role in multi-drug resistance (MDR) to anti-cancer drugs and drug-drug interactions. The prediction of BCRP inhibition can facilitate evaluating potential drug resistance and drug-drug interactions in early stage of drug discovery. Here we reported a structurally diverse dataset consisting of 1098 BCRP inhibitors and 1701 non-inhibitors. Analysis of various physicochemical properties illustrates that BCRP inhibitors are more hydrophobic and aromatic than non-inhibitors. We then developed a series of quantitative structure-activity relationship (QSAR) models to discriminate between BCRP inhibitors and non-inhibitors. The optimal feature subset was determined by a wrapper feature selection method named rfSA (simulated annealing algorithm coupled with random forest), and the classification models were established by using seven machine learning approaches based on the optimal feature subset, including a deep learning method, two ensemble learning methods, and four classical machine learning methods. The statistical results demonstrated that three methods, including support vector machine (SVM), deep neural networks (DNN) and extreme gradient boosting (XGBoost), outperformed the others, and the SVM classifier yielded the best predictions (MCC?=?0.812 and AUC?=?0.958 for the test set). Then, a perturbation-based model-agnostic method was used to interpret our models and analyze the representative features for different models. The application domain analysis demonstrated the prediction reliability of our models. Moreover, the important structural fragments related to BCRP inhibition were identified by the information gain (IG) method along with the frequency analysis. In conclusion, we believe that the classification models developed in this study can be regarded as simple and accurate tools to distinguish BCRP inhibitors from non-inhibitors in drug design and discovery pipelines.

SUBMITTER: Jiang D

PROVIDER: S-EPMC7059329 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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ADMET evaluation in drug discovery. 20. Prediction of breast cancer resistance protein inhibition through machine learning.

Jiang Dejun D Lei Tailong T Wang Zhe Z Shen Chao C Cao Dongsheng D Hou Tingjun T

Journal of cheminformatics 20200305 1

Breast cancer resistance protein (BCRP/ABCG2), an ATP-binding cassette (ABC) efflux transporter, plays a critical role in multi-drug resistance (MDR) to anti-cancer drugs and drug-drug interactions. The prediction of BCRP inhibition can facilitate evaluating potential drug resistance and drug-drug interactions in early stage of drug discovery. Here we reported a structurally diverse dataset consisting of 1098 BCRP inhibitors and 1701 non-inhibitors. Analysis of various physicochemical properties ...[more]

PMID: 33430990

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Project description:MOTIVATION:Artificial intelligence, trained via machine learning (e.g. neural nets, random forests) or computational statistical algorithms (e.g. support vector machines, ridge regression), holds much promise for the improvement of small-molecule drug discovery. However, small-molecule structure-activity data are high dimensional with low signal-to-noise ratios and proper validation of predictive methods is difficult. It is poorly understood which, if any, of the currently available machine learning algorithms will best predict new candidate drugs. RESULTS:The quantile-activity bootstrap is proposed as a new model validation framework using quantile splits on the activity distribution function to construct training and testing sets. In addition, we propose two novel rank-based loss functions which penalize only the out-of-sample predicted ranks of high-activity molecules. The combination of these methods was used to assess the performance of neural nets, random forests, support vector machines (regression) and ridge regression applied to 25 diverse high-quality structure-activity datasets publicly available on ChEMBL. Model validation based on random partitioning of available data favours models that overfit and 'memorize' the training set, namely random forests and deep neural nets. Partitioning based on quantiles of the activity distribution correctly penalizes extrapolation of models onto structurally different molecules outside of the training data. Simpler, traditional statistical methods such as ridge regression can outperform state-of-the-art machine learning methods in this setting. In addition, our new rank-based loss functions give considerably different results from mean squared error highlighting the necessity to define model optimality with respect to the decision task at hand. AVAILABILITY AND IMPLEMENTATION:All software and data are available as Jupyter notebooks found at https://github.com/owatson/QuantileBootstrap. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.

Dataset Information

ADMET evaluation in drug discovery. 20. Prediction of breast cancer resistance protein inhibition through machine learning.

Publications

ADMET evaluation in drug discovery. 20. Prediction of breast cancer resistance protein inhibition through machine learning.

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