<b>Network approaches to drug discovery</b>

Chandra, Nagasuma; Padiadpu, Jyothi

doi:10.1517/17460441.2013.741119

Cited by 39 publications

(35 citation statements)

References 105 publications

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“…Systems chemo-biology tools allow prospecting of new drug targets and interaction between chemical compounds and biological networks (Chandra and Padiadpu, 2013;Csermely et al, 2013;Schneider and Klabunde, 2013). Our group has successfully employed systems chemo-biology to discover potential new anti-tumor drugs for gastric cancer (Rosado et al, 2011) and to understand the molecular pathways underlying fetal malformations associated with tobacco abuse during pregnancy (Feltes et al, 2013).…”

Section: Design Of the Interactome Network Topological Analysis Andmentioning

confidence: 99%

Fetal Alcohol Syndrome, Chemo-Biology and OMICS: Ethanol Effects on Vitamin Metabolism During Neurodevelopment as Measured by Systems Biology Analysis

Feltes

Poloni

Nunes

et al. 2014

OMICS: A Journal of Integrative Biology

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Fetal alcohol syndrome (FAS) is a prenatal disease characterized by fetal morphological and neurological abnormalities originating from exposure to alcohol. Although FAS is a well-described pathology, the molecular mechanisms underlying its progression are virtually unknown. Moreover, alcohol abuse can affect vitamin metabolism and absorption, although how alcohol impairs such biochemical pathways remains to be elucidated. We employed a variety of systems chemo-biology tools to understand the interplay between ethanol metabolism and vitamins during mouse neurodevelopment. For this purpose, we designed interactomes and employed transcriptomic data analysis approaches to study the neural tissue of Mus musculus exposed to ethanol prenatally and postnatally, simulating conditions that could lead to FAS development at different life stages. Our results showed that FAS can promote early changes in neurotransmitter release and glutamate equilibrium, as well as an abnormal calcium influx that can lead to neuroinflammation and impaired neurodifferentiation, both extensively connected with vitamin action and metabolism. Genes related to retinoic acid, niacin, vitamin D, and folate metabolism were underexpressed during neurodevelopment and appear to contribute to neuroinflammation progression and impaired synapsis. Our results also indicate that genes coding for tubulin, tubulinassociated proteins, synapse plasticity proteins, and proteins related to neurodifferentiation are extensively affected by ethanol exposure. Finally, we developed a molecular model of how ethanol can affect vitamin metabolism and impair neurodevelopment.

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Section: Design Of the Interactome Network Topological Analysis Andmentioning

confidence: 99%

Fetal Alcohol Syndrome, Chemo-Biology and OMICS: Ethanol Effects on Vitamin Metabolism During Neurodevelopment as Measured by Systems Biology Analysis

Feltes

Poloni

Nunes

et al. 2014

OMICS: A Journal of Integrative Biology

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“…An important criterion to consider during drug target identification is that the target is chemically tractable and should be sufficiently different from that of any host protein (84). Chemical tractability, or druggability, can be translated into a problem of identifying whether a protein has a binding site capable of recognizing a small molecule ligand with reasonable affinity and whether the site and hence the binding is specific enough, especially compared to host proteins.…”

Section: New Target Identification: Structural Assessment Of Druggabimentioning

confidence: 99%

Structural Annotation of the Mycobacterium tuberculosis Proteome

Chandra

Sandhya

2014

Microbiol Spectr

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Efforts from the TB Structural Genomics Consortium together with those of tuberculosis structural biologists worldwide have led to the determination of about 350 structures, making up nearly a tenth of the pathogen's proteome. Given that knowledge of protein structures is essential to obtaining a high-resolution understanding of the underlying biology, it is desirable to have a structural view of the entire proteome. Indeed, structure prediction methods have advanced sufficiently to allow structural models of many more proteins to be built based on homology modeling and fold recognition strategies. By means of these approaches, structural models for about 2,877 proteins, making up nearly 70% of the Mycobacterium tuberculosis proteome, are available. Knowledge from bioinformatics has made significant inroads into an improved annotation of the M. tuberculosis genome and in the prediction of key protein players that interact in vital pathways, some of which are unique to the organism. Functional inferences have been made for a large number of proteins based on fold-function associations. More importantly, ligand-binding pockets of the proteins are identified and scanned against a large database, leading to binding site–based ligand associations and hence structure-based function annotation. Near proteome-wide structural models provide a global perspective of the fold distribution in the genome. New insights about the folds that predominate in the genome, as well as the fold combinations that make up multidomain proteins, are also obtained. This chapter describes the structural proteome, functional inferences drawn from it, and its applications in drug discovery.

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“…The topological analysis of large networks of biomolecule interactions has contributed to the functional prediction of biological and pharmacological propensities of novel genes or proteins [6–8]. However, several functions of proteins have yet to be fully elucidated or even predicted.…”

Section: Introductionmentioning

confidence: 99%

“…Networks have proven to be a useful mathematical artifact for studying complex systems in multiple disciplines such as economics, sociology, and biology [2,6,8,9]. The term biological network refers to networks that describe relationships among a set of elements within biological systems.…”

Section: Introductionmentioning

confidence: 99%

The G Protein-Coupled Receptor Heterodimer Network (GPCR-HetNet) and Its Hub Components

Borroto-Escuela

Brito

Romero-Fernández

et al. 2014

IJMS

123

110

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G protein-coupled receptors (GPCRs) oligomerization has emerged as a vital characteristic of receptor structure. Substantial experimental evidence supports the existence of GPCR-GPCR interactions in a coordinated and cooperative manner. However, despite the current development of experimental techniques for large-scale detection of GPCR heteromers, in order to understand their connectivity it is necessary to develop novel tools to study the global heteroreceptor networks. To provide insight into the overall topology of the GPCR heteromers and identify key players, a collective interaction network was constructed. Experimental interaction data for each of the individual human GPCR protomers was obtained manually from the STRING and SCOPUS databases. The interaction data were used to build and analyze the network using Cytoscape software. The network was treated as undirected throughout the study. It is comprised of 156 nodes, 260 edges and has a scale-free topology. Connectivity analysis reveals a significant dominance of intrafamily versus interfamily connections. Most of the receptors within the network are linked to each other by a small number of edges. DRD2, OPRM, ADRB2, AA2AR, AA1R, OPRK, OPRD and GHSR are identified as hubs. In a network representation 10 modules/clusters also appear as a highly interconnected group of nodes. Information on this GPCR network can improve our understanding of molecular integration. GPCR-HetNet has been implemented in Java and is freely available at http://www.iiia.csic.es/~ismel/GPCR-Nets/index.html.

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Network approaches to drug discovery

Cited by 39 publications

References 105 publications

Fetal Alcohol Syndrome, Chemo-Biology and OMICS: Ethanol Effects on Vitamin Metabolism During Neurodevelopment as Measured by Systems Biology Analysis

Fetal Alcohol Syndrome, Chemo-Biology and OMICS: Ethanol Effects on Vitamin Metabolism During Neurodevelopment as Measured by Systems Biology Analysis

Structural Annotation of the Mycobacterium tuberculosis Proteome

The G Protein-Coupled Receptor Heterodimer Network (GPCR-HetNet) and Its Hub Components

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