Dataset Information

Analysis of Biological Screening Compounds with Single- or Multi-Target Activity via Diagnostic Machine Learning.

ABSTRACT: Predicting compounds with single- and multi-target activity and exploring origins of compound specificity and promiscuity is of high interest for chemical biology and drug discovery. We present a large-scale analysis of compound promiscuity including two major components. First, high-confidence datasets of compounds with multi- and corresponding single-target activity were extracted from biological screening data. Positive and negative assay results were taken into account and data completeness was ensured. Second, these datasets were investigated using diagnostic machine learning to systematically distinguish between compounds with multi- and single-target activity. Models built on the basis of chemical structure consistently produced meaningful predictions. These findings provided evidence for the presence of structural features differentiating promiscuous and non-promiscuous compounds. Machine learning under varying conditions using modified datasets revealed a strong influence of nearest neighbor relationship on the predictions. Many multi-target compounds were found to be more similar to other multi-target compounds than single-target compounds and vice versa, which resulted in consistently accurate predictions. The results of our study confirm the presence of structural relationships that differentiate promiscuous and non-promiscuous compounds.

SUBMITTER: Feldmann C

PROVIDER: S-EPMC7761051 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Analysis of Biological Screening Compounds with Single- or Multi-Target Activity via Diagnostic Machine Learning.

Feldmann Christian C Yonchev Dimitar D Bajorath Jürgen J

Biomolecules 20201127 12

Predicting compounds with single- and multi-target activity and exploring origins of compound specificity and promiscuity is of high interest for chemical biology and drug discovery. We present a large-scale analysis of compound promiscuity including two major components. First, high-confidence datasets of compounds with multi- and corresponding single-target activity were extracted from biological screening data. Positive and negative assay results were taken into account and data completeness ...[more]

PMID: 33260876

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Project description:Background:Epilepsy is a disorder that can manifest as abnormalities in neurological or physical function. Stress cardiomyopathy is closely associated with neurological stimulation. However, the mechanisms underlying the interrelationship between epilepsy and stress cardiomyopathy are unclear. This paper aims to explore the genetic features and potential molecular mechanisms shared in epilepsy and stress cardiomyopathy. Methods:By analyzing the epilepsy dataset and stress cardiomyopathy dataset separately, the intersection of the two disease co-expressed differential genes is obtained, the co-expressed differential genes reveal the biological functions, the network is constructed, and the core modules are identified to reveal the interaction mechanism, the co-expressed genes with diagnostic validity are screened by machine learning algorithms, and the co-expressed genes are validated in parallel on the epilepsy single-cell data and the stress cardiomyopathy rat model. Results: Epilepsy causes stress cardiomyopathy, and its key pathways are Complement and coagulation cascades, HIF-1 signaling pathway, its key co-expressed genes include SPOCK2, CTSZ, HLA-DMB, ALDOA, SFRP1, ERBB3.The key immune cell subpopulations localized by single-cell data are the T_cells subgroup, Microglia subgroup, Macrophage subgroup, Astrocyte subgroup, and Oligodendrocytes subgroup. Conclusion: We believe epilepsy causing stress cardiomyopathy results from a multi-gene, multi-pathway combination. We identified the core co-expressed genes (SPOCK2, CTSZ, HLA-DMB, ALDOA, SFRP1, ERBB3) and the pathways that function in them (Complement and coagulation cascades, HIF-1 signaling pathway,JAK-STAT signaling pathway), and finally localized their key cellular subgroups(T_cells subgroup, Microglia subgroup, Macrophage subgroup, Astrocyte subgroup,and Oligodendrocytes subgroup). Also, combining cell subpopulations with hypercoagulability as well as sympathetic excitation further narrowed the cell subpopulations of related functions.

Project description:BackgroundDrug repositioning, also known as drug repurposing, defines new indications for existing drugs and can be used as an alternative to drug development. In recent years, the accumulation of large volumes of information related to drugs and diseases has led to the development of various computational approaches for drug repositioning. Although herbal medicines have had a great impact on current drug discovery, there are still a large number of herbal compounds that have no definite indications.ResultsIn the present study, we constructed a computational model to predict the unknown pharmacological effects of herbal compounds using machine learning techniques. Based on the assumption that similar diseases can be treated with similar drugs, we used four categories of drug-drug similarity (e.g., chemical structure, side-effects, gene ontology, and targets) and three categories of disease-disease similarity (e.g., phenotypes, human phenotype ontology, and gene ontology). Then, associations between drug and disease were predicted using the employed similarity features. The prediction models were constructed using classification algorithms, including logistic regression, random forest and support vector machine algorithms. Upon cross-validation, the random forest approach showed the best performance (AUC = 0.948) and also performed well in an external validation assessment using an unseen independent dataset (AUC = 0.828). Finally, the constructed model was applied to predict potential indications for existing drugs and herbal compounds. As a result, new indications for 20 existing drugs and 31 herbal compounds were predicted and validated using clinical trial data.ConclusionsThe predicted results were validated manually confirming the performance and underlying mechanisms - for example, irinotecan as a treatment for neuroblastoma. From the prediction, herbal compounds were considered to be drug candidates for related diseases which is important to be further developed. The proposed prediction model can contribute to drug discovery by suggesting drug candidates from herbal compounds which have potentials but few were studied.

Dataset Information

Analysis of Biological Screening Compounds with Single- or Multi-Target Activity via Diagnostic Machine Learning.

Publications

Analysis of Biological Screening Compounds with Single- or Multi-Target Activity via Diagnostic Machine Learning.

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