The Mycobacterium tuberculosis Drugome and Its Polypharmacological Implications
| Autor: | Li Xie, Sarah L. Kinnings, Lei Xie, Kingston H. Fung, Phillip e. Bourne, Richard M. Jackson |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Databases
Factual Systems biology Druggability Antitubercular Agents Computational Biology/Macromolecular Structure Analysis Genomics Computational biology Bioinformatics Models Biological Mycobacterium tuberculosis 03 medical and health sciences Cellular and Molecular Neuroscience Structural bioinformatics 0302 clinical medicine Bacterial Proteins Interaction network Genetics Cluster Analysis Humans Tuberculosis Computer Simulation Molecular Targeted Therapy Molecular Biology lcsh:QH301-705.5 Biotechnology/Small Molecule Chemistry Ecology Evolution Behavior and Systematics 030304 developmental biology 0303 health sciences Computational Biology/Systems Biology Binding Sites Ecology biology Drug discovery Computational Biology Reproducibility of Results biology.organism_classification 3. Good health Computational Theory and Mathematics Structural biology lcsh:Biology (General) Modeling and Simulation 030217 neurology & neurosurgery Research Article |
| Zdroj: | PLoS Computational Biology PLoS Computational Biology, Vol 6, Iss 11, p e1000976 (2010) |
| ISSN: | 1553-7358 1553-734X |
| Popis: | We report a computational approach that integrates structural bioinformatics, molecular modelling and systems biology to construct a drug-target network on a structural proteome-wide scale. The approach has been applied to the genome of Mycobacterium tuberculosis (M.tb), the causative agent of one of today's most widely spread infectious diseases. The resulting drug-target interaction network for all structurally characterized approved drugs bound to putative M.tb receptors, we refer to as the ‘TB-drugome’. The TB-drugome reveals that approximately one-third of the drugs examined have the potential to be repositioned to treat tuberculosis and that many currently unexploited M.tb receptors may be chemically druggable and could serve as novel anti-tubercular targets. Furthermore, a detailed analysis of the TB-drugome has shed new light on the controversial issues surrounding drug-target networks [1]–[3]. Indeed, our results support the idea that drug-target networks are inherently modular, and further that any observed randomness is mainly caused by biased target coverage. The TB-drugome (http://funsite.sdsc.edu/drugome/TB) has the potential to be a valuable resource in the development of safe and efficient anti-tubercular drugs. More generally the methodology may be applied to other pathogens of interest with results improving as more of their structural proteomes are determined through the continued efforts of structural biology/genomics. Author Summary The worldwide increase in multi-drug resistant TB poses a great threat to human health and highlights the need to identify new anti-tubercular agents. We have developed a computational strategy to link the structural proteome of Mycobacterium tuberculosis, the causative agent of tuberculosis, to all structurally characterized approved drugs, and hence construct a proteome-wide drug-target network – the TB-drugome. The TB-drugome has the potential to be a valuable resource in the development of safe and efficient anti-tubercular drugs. More generally, the proteome-wide and multi-scale view of target and drug space may facilitate a systematic drug discovery process, which concurrently takes into account the disease mechanism and druggability of targets, the drug-likeness and ADMET properties of chemical compounds, and the genetic dispositions of individuals. Ultimately it may help to reduce the high attrition rate in drug development through a better understanding of drug-receptor interactions on a large scale. |
| Databáze: | OpenAIRE |
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