Improving (Q)SAR predictions by examining bias in the selection of compounds for experimental testing |
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Authors: | P.V. Pogodin A.A. Lagunin D.A. Filimonov M.C. Nicklaus V.V. Poroikov |
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Affiliation: | 1. Department of Bioinformatics, Institute of Biomedical Chemistry, Moscow, Russiapogodinpv@gmail.com;3. Department of Bioinformatics, Institute of Biomedical Chemistry, Moscow, Russia;4. Department of Bioinformatics, Medical-Biological Department, Pirogov Russian National Research Medical University, Moscow, Russiahttps://orcid.org/0000-0003-1757-8004;5. Department of Bioinformatics, Institute of Biomedical Chemistry, Moscow, Russiahttps://orcid.org/0000-0002-0339-8478;6. Computer-Aided Drug Design Group, Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, NIH, NCI-Frederick, Frederick, MD, USA;7. Department of Bioinformatics, Institute of Biomedical Chemistry, Moscow, Russiahttps://orcid.org/0000-0001-7937-2621 |
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Abstract: | ABSTRACTExisting data on structures and biological activities are limited and distributed unevenly across distinct molecular targets and chemical compounds. The question arises if these data represent an unbiased sample of the general population of chemical-biological interactions. To answer this question, we analyzed ChEMBL data for 87,583 molecules tested against 919 protein targets using supervised and unsupervised approaches. Hierarchical clustering of the Murcko frameworks generated using Chemistry Development Toolkit showed that the available data form a big diffuse cloud without apparent structure. In contrast hereto, PASS-based classifiers allowed prediction whether the compound had been tested against the particular molecular target, despite whether it was active or not. Thus, one may conclude that the selection of chemical compounds for testing against specific targets is biased, probably due to the influence of prior knowledge. We assessed the possibility to improve (Q)SAR predictions using this fact: PASS prediction of the interaction with the particular target for compounds predicted as tested against the target has significantly higher accuracy than for those predicted as untested (average ROC AUC are about 0.87 and 0.75, respectively). Thus, considering the existing bias in the data of the training set may increase the performance of virtual screening. |
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Keywords: | Ligand-target interaction (Q)SAR training set compound selection bias accuracy of prediction applicability domain virtual screening SAVI library |
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