Dataset Information

Orthologue chemical space and its influence on target prediction.

ABSTRACT:

Motivation

In silico approaches often fail to utilize bioactivity data available for orthologous targets due to insufficient evidence highlighting the benefit for such an approach. Deeper investigation into orthologue chemical space and its influence toward expanding compound and target coverage is necessary to improve the confidence in this practice.

Results

Here we present analysis of the orthologue chemical space in ChEMBL and PubChem and its impact on target prediction. We highlight the number of conflicting bioactivities between human and orthologues is low and annotations are overall compatible. Chemical space analysis shows orthologues are chemically dissimilar to human with high intra-group similarity, suggesting they could effectively extend the chemical space modelled. Based on these observations, we show the benefit of orthologue inclusion in terms of novel target coverage. We also benchmarked predictive models using a time-series split and also using bioactivities from Chemistry Connect and HTS data available at AstraZeneca, showing that orthologue bioactivity inclusion statistically improved performance.

Availability and implementation

Orthologue-based bioactivity prediction and the compound training set are available at www.github.com/lhm30/PIDGINv2.

Contact

ab454@cam.ac.uk.

Supplementary information

Supplementary data are available at Bioinformatics online.

SUBMITTER: Mervin LH

PROVIDER: S-EPMC5870859 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Publications

Orthologue chemical space and its influence on target prediction.

Mervin Lewis H LH Bulusu Krishna C KC Kalash Leen L Afzal Avid M AM Svensson Fredrik F Firth Mike A MA Barrett Ian I Engkvist Ola O Bender Andreas A

Bioinformatics (Oxford, England) 20180101 1

<h4>Motivation</h4>In silico approaches often fail to utilize bioactivity data available for orthologous targets due to insufficient evidence highlighting the benefit for such an approach. Deeper investigation into orthologue chemical space and its influence toward expanding compound and target coverage is necessary to improve the confidence in this practice.<h4>Results</h4>Here we present analysis of the orthologue chemical space in ChEMBL and PubChem and its impact on target prediction. We hig ...[more]

PMID: 28961699

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Project description:BACKGROUND:In silico analyses are increasingly being used to support mode-of-action investigations; however many such approaches do not utilise the large amounts of inactive data held in chemogenomic repositories. The objective of this work is concerned with the integration of such bioactivity data in the target prediction of orphan compounds to produce the probability of activity and inactivity for a range of targets. To this end, a novel human bioactivity data set was constructed through the assimilation of over 195 million bioactivity data points deposited in the ChEMBL and PubChem repositories, and the subsequent application of a sphere-exclusion selection algorithm to oversample presumed inactive compounds. RESULTS:A Bernoulli Naïve Bayes algorithm was trained using the data and evaluated using fivefold cross-validation, achieving a mean recall and precision of 67.7 and 63.8 % for active compounds and 99.6 and 99.7 % for inactive compounds, respectively. We show the performances of the models are considerably influenced by the underlying intraclass training similarity, the size of a given class of compounds, and the degree of additional oversampling. The method was also validated using compounds extracted from WOMBAT producing average precision-recall AUC and BEDROC scores of 0.56 and 0.85, respectively. Inactive data points used for this test are based on presumed inactivity, producing an approximated indication of the true extrapolative ability of the models. A distance-based applicability domain analysis was also conducted; indicating an average Tanimoto Coefficient distance of 0.3 or greater between a test and training set can be used to give a global measure of confidence in model predictions. A final comparison to a method trained solely on active data from ChEMBL performed with precision-recall AUC and BEDROC scores of 0.45 and 0.76. CONCLUSIONS:The inclusion of inactive data for model training produces models with superior AUC and improved early recognition capabilities, although the results from internal and external validation of the models show differing performance between the breadth of models. The realised target prediction protocol is available at https://github.com/lhm30/PIDGIN.Graphical abstractThe inclusion of large scale negative training data for in silico target prediction improves the precision and recall AUC and BEDROC scores for target models.

Dataset Information

Orthologue chemical space and its influence on target prediction.

Motivation

Results

Availability and implementation

Contact

Supplementary information

Publications

Orthologue chemical space and its influence on target prediction.

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