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Mining large-scale response networks reveals 'topmost activities' in Mycobacterium tuberculosis infection.

ABSTRACT: Mycobacterium tuberculosis owes its high pathogenic potential to its ability to evade host immune responses and thrive inside the macrophage. The outcome of infection is largely determined by the cellular response comprising a multitude of molecular events. The complexity and inter-relatedness in the processes makes it essential to adopt systems approaches to study them. In this work, we construct a comprehensive network of infection-related processes in a human macrophage comprising 1888 proteins and 14,016 interactions. We then compute response networks based on available gene expression profiles corresponding to states of health, disease and drug treatment. We use a novel formulation for mining response networks that has led to identifying highest activities in the cell. Highest activity paths provide mechanistic insights into pathogenesis and response to treatment. The approach used here serves as a generic framework for mining dynamic changes in genome-scale protein interaction networks.

SUBMITTER: Sambarey A

PROVIDER: S-EPMC3725478 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Mining large-scale response networks reveals 'topmost activities' in Mycobacterium tuberculosis infection.

Sambarey Awanti A Prashanthi Karyala K Chandra Nagasuma N

Scientific reports 20130101

Mycobacterium tuberculosis owes its high pathogenic potential to its ability to evade host immune responses and thrive inside the macrophage. The outcome of infection is largely determined by the cellular response comprising a multitude of molecular events. The complexity and inter-relatedness in the processes makes it essential to adopt systems approaches to study them. In this work, we construct a comprehensive network of infection-related processes in a human macrophage comprising 1888 protei ...[more]

PMID: 23892477

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Project description:BACKGROUND: The Pubchem Database is a large-scale resource for chemical information, containing millions of chemical compound activities derived by high-throughput screening (HTS). The ability to extract characteristic substructures from such enormous amounts of data is steadily growing in importance. Compounds with shared basic active structures (BASs) exhibiting G-protein coupled receptor (GPCR) activity and repeated dose toxicity have been mined from small datasets. However, the mining process employed was not applicable to large datasets owing to a large imbalance between the numbers of active and inactive compounds. In most datasets, one active compound will appear for every 1000 inactive compounds. Most mining techniques work well only when these numbers are similar. RESULTS: This difficulty was overcome by sampling an equal number of active and inactive compounds. The sampling process was repeated to maintain the structural diversity of the inactive compounds. An interactive KNIME workflow that enabled effective sampling and data cleaning processes was created. The application of the cascade model and subsequent structural refinement yielded the BAS candidates. Repeated sampling increased the ratio of active compounds containing these substructures. Three samplings were deemed adequate to identify all of the meaningful BASs. BASs expressing similar structures were grouped to give the final set of BASs. This method was applied to HIV integrase and protease inhibitor activities in the MDL Drug Data Report (MDDR) database and to procaspase-3 activators in the PubChem BioAssay database, yielding 14, 12, and 18 BASs, respectively. CONCLUSIONS: The proposed mining scheme successfully extracted meaningful substructures from large datasets of chemical structures. The resulting BASs were deemed reasonable by an experienced medicinal chemist. The mining itself requires about 3 days to extract BASs with a given physiological activity. Thus, the method described herein is an effective way to analyze large HTS databases.

Dataset Information

Mining large-scale response networks reveals 'topmost activities' in Mycobacterium tuberculosis infection.

Publications

Mining large-scale response networks reveals 'topmost activities' in Mycobacterium tuberculosis infection.

Similar Datasets

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