T3DB: a comprehensively annotated database of common toxins and their targets

Lim, Emilia L.; Pon, Allison; Djoumbou, Yannick; Knox, Craig; Shrivastava, Savita; Guo, An Chi; Neveu, Vanessa; Wishart, David S.

doi:10.1093/nar/gkp934

Cited by 130 publications

(91 citation statements)

References 15 publications

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“…Combined with the fact that similar pockets occur across many different types of protein structures with similar patterns of amino acid conservation, we conclude that ligand-binding promiscuity is likely an inherent feature resulting from the geometric and physical-chemical properties of proteins. This promiscuity implies that the notion of one molecule-one protein target that underlies many aspects of drug discovery is likely incorrect, a conclusion consistent with recent studies (26,30,31). Moreover, within a cell, a given endogenous ligand likely interacts at low levels with multiple proteins that may have different global structures.…”

Section: Discussionmentioning

confidence: 91%

Interplay of physics and evolution in the likely origin of protein biochemical function

Skolnick

Gao

2013

Proc. Natl. Acad. Sci. U.S.A.

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The intrinsic ability of protein structures to exhibit the geometric and sequence properties required for ligand binding without evolutionary selection is shown by the coincidence of the properties of pockets in native, single domain proteins with those in computationally generated, compact homopolypeptide, artificial (ART) structures. The library of native pockets is covered by a remarkably small number of representative pockets (∼400), with virtually every native pocket having a statistically significant match in the ART library, suggesting that the library is complete. When sequences are selected for ART structures based on fold stability, pocket sequence conservation is coincident to native. The fact that structurally and sequentially similar pockets occur across fold classes combined with the small number of representative pockets in native proteins implies that promiscuous interactions are inherent to proteins. Based on comparison of PDB (real, single domain protein structures found in the Protein Data Bank) and ART structures and pockets, the widespread assumption that the co-occurrence of global structure, pocket similarity, and amino acid conservation demands an evolutionary relationship between proteins is shown to significantly underestimate the random background probability. Indeed, many features of biochemical function arise from the physical properties of proteins that evolution likely fine-tunes to achieve specificity. Finally, our study suggests that a repertoire of thermodynamically (marginally) stable proteins could engage in many of the biochemical reactions needed for living systems without selection for function, a conclusion with significant implications for the origin of life.protein evolution | protein pocket space | protein-ligand interactions

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Section: Discussionmentioning

confidence: 91%

Interplay of physics and evolution in the likely origin of protein biochemical function

Skolnick

Gao

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…T3DB [99] www.t3db.org ∼ 3,600 common toxins and environmental pollutants FooDB [100] www.foodb.ca ∼ 28,000 food components/additives, with presumptive health effects UMCD [101] umcd.humanconnectomeproject.org 1,887 brain connectivity matrices from neuroimaging data HCP [102] www.humanconnectome.org/data MRI captured brain connectivity maps of 500 adult individuals HMP [103] hmpdacc.org 11,000 samples of human microbiomes from 300 adult individuals Inference of patient-specific pathways and patient stratification by integrating DNA copy number variations and mRNA expression data. Matrix Factorization unsupervised iCluster [124] Cancer patient stratification by integrating copy number variation and mRNA expression data.…”

Section: Databasementioning

confidence: 99%

Integrative methods for analyzing big data in precision medicine

2016

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We provide an overview of recent developments in big data analyses in the context of precision medicine and health informatics. With the advance in technologies capturing molecular and medical data, we entered the area of Big Data in biology and medicine. These data offer many opportunities to advance precision medicine.We outline key challenges in precision medicine and present recent advances in data integrationbased methods to uncover personalized information from big data produced by various omics studies. We survey recent integrative methods for disease subtyping, bio-markers discovery and drug repurposing, and list the tools that are available to domain scientists. Given the ever-growing nature of these big data, we highlight key issues that big data integration methods will face.

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“…Secondly, many toxicology related databases, such as the T3 (Toxin and Toxin Targets) database (Lim et al, 2010), have extensive documentation on various toxins and their biological targets, but the information is not available in a manner that facilitates a systems-based approach. For example, informative descriptions are often provided as free text, which is not machine-readable and does not use a structured vocabulary or ontology to describe mechanisms and targets.…”

Section: What Gap Could a Pot Database Fill That Is Not Met By Exismentioning

confidence: 99%

Pathways of Toxicity

Kleensang

Maertens

Rosenberg

et al. 2014

ALTEX

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Summary Despite wide-spread consensus on the need to transform toxicology and risk assessment in order to keep pace with technological and computational changes that have revolutionized the life sciences, there remains much work to be done to achieve the vision of toxicology based on a mechanistic foundation. A workshop was organized to explore one key aspect of this transformation – the development of Pathways of Toxicity (PoT) as a key tool for hazard identification based on systems biology. Several issues were discussed in depth in the workshop: The first was the challenge of formally defining the concept of a PoT as distinct from, but complementary to, other toxicological pathway concepts such as mode of action (MoA). The workshop came up with a preliminary definition of PoT as “A molecular definition of cellular processes shown to mediate adverse outcomes of toxicants”. It is further recognized that normal physiological pathways exist that maintain homeostasis and these, sufficiently perturbed, can become PoT. Second, the workshop sought to define the adequate public and commercial resources for PoT information, including data, visualization, analyses, tools, and use-cases, as well as the kinds of efforts that will be necessary to enable the creation of such a resource. Third, the workshop explored ways in which systems biology approaches could inform pathway annotation, and which resources are needed and available that can provide relevant PoT information to the diverse user communities.

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T3DB: a comprehensively annotated database of common toxins and their targets

Cited by 130 publications

References 15 publications

Interplay of physics and evolution in the likely origin of protein biochemical function

Interplay of physics and evolution in the likely origin of protein biochemical function

Integrative methods for analyzing big data in precision medicine

Pathways of Toxicity

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