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An integrative approach to develop computational pipeline for drug-target interaction network analysis.

ABSTRACT: Understanding the general principles governing the functioning of biological networks is a major challenge of the current era. Functionality of biological networks can be observed from drug and target interaction perspective. All possible modes of operations of biological networks are confined by the interaction analysis. Several of the existing approaches in this direction, however, are data-driven and thus lack potential to be generalized and extrapolated to different species. In this paper, we demonstrate a systems pharmacology pipeline and discuss how the network theory, along with gene ontology (GO) analysis, co-expression analysis, module re-construction, pathway mapping and structure level analysis can be used to decipher important properties of biological networks with the aim to propose lead molecule for the therapeutic interventions of various diseases.

SUBMITTER: Bansal A

PROVIDER: S-EPMC6035197 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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An integrative approach to develop computational pipeline for drug-target interaction network analysis.

Bansal Ankush A Srivastava Pulkit Anupam PA Singh Tiratha Raj TR

Scientific reports 20180706 1

Understanding the general principles governing the functioning of biological networks is a major challenge of the current era. Functionality of biological networks can be observed from drug and target interaction perspective. All possible modes of operations of biological networks are confined by the interaction analysis. Several of the existing approaches in this direction, however, are data-driven and thus lack potential to be generalized and extrapolated to different species. In this paper, w ...[more]

PMID: 29980766

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Project description:Due to relatively high costs and labor required for experimental profiling of the full target space of chemical compounds, various machine learning models have been proposed as cost-effective means to advance this process in terms of predicting the most potent compound-target interactions for subsequent verification. However, most of the model predictions lack direct experimental validation in the laboratory, making their practical benefits for drug discovery or repurposing applications largely unknown. Here, we therefore introduce and carefully test a systematic computational-experimental framework for the prediction and pre-clinical verification of drug-target interactions using a well-established kernel-based regression algorithm as the prediction model. To evaluate its performance, we first predicted unmeasured binding affinities in a large-scale kinase inhibitor profiling study, and then experimentally tested 100 compound-kinase pairs. The relatively high correlation of 0.77 (p < 0.0001) between the predicted and measured bioactivities supports the potential of the model for filling the experimental gaps in existing compound-target interaction maps. Further, we subjected the model to a more challenging task of predicting target interactions for such a new candidate drug compound that lacks prior binding profile information. As a specific case study, we used tivozanib, an investigational VEGF receptor inhibitor with currently unknown off-target profile. Among 7 kinases with high predicted affinity, we experimentally validated 4 new off-targets of tivozanib, namely the Src-family kinases FRK and FYN A, the non-receptor tyrosine kinase ABL1, and the serine/threonine kinase SLK. Our sub-sequent experimental validation protocol effectively avoids any possible information leakage between the training and validation data, and therefore enables rigorous model validation for practical applications. These results demonstrate that the kernel-based modeling approach offers practical benefits for probing novel insights into the mode of action of investigational compounds, and for the identification of new target selectivities for drug repurposing applications.

Dataset Information

An integrative approach to develop computational pipeline for drug-target interaction network analysis.

Publications

An integrative approach to develop computational pipeline for drug-target interaction network analysis.

Similar Datasets

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