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Metabolomics and Drug Discovery ©  All rights reserved P. Paulsharma Chakravarthy, School of Genomics, Loyola College www....
Metabolomics….. <ul><li>Metabolomics is the study of metabolite profiles in biological samples, particularly urine, saliva...
Metabolomics vs. other “omic” sciences <ul><li>Metabolite profile profiles provides knowledge and information rather than ...
<ul><li>Metabolic profiling, the elucidation of the small molecule components of a cell,  tissue or organism, has emerged ...
<ul><li>The Metabolome gives a direct picture of the cells activity and its environment. It presents a powerful portrait, ...
Future Perspectives <ul><li>Detection of unusual metabolitic profile will aid in early cancer detection </li></ul><ul><li>...
Metabolism Basics….. <ul><li>Definition - Metabolic pathways   </li></ul><ul><li>Is a series of consecutive enzymatic reac...
Study of Metabolome - In terms of sequence of reactions by which a specific nutrients is converted to end products, and th...
<ul><li>Metabolic Inhibitors, growth studies and Biochemical Genetics </li></ul><ul><li>Isotopes in Biochemistry </li></ul...
Metabolic Pathway Databases
Representation of Pathways…
Gene Information - KEGG
Genome Map Representation - KEGG
<ul><ul><ul><ul><ul><li>Pathway Assist </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Transpath </li></ul></ul></ul...
Practical Approaches <ul><li>Unique Biomolecules </li></ul><ul><li>Biosynthetic Pathway Targets </li></ul>
A Practical Example  - Mycobacterium tuberculosis H37Rv <ul><li>Pathogenesis Process </li></ul><ul><li>Cell Wall Confers T...
<ul><li>If only one enzyme-encoding gene out of a pathway of several steps is found in an annotated genome, it is likely t...
Isoprenoids
Screening for Drug Target Pathways
DOXP and Mevalonate Pathway
Screening for Drug Target Pathways
+ + + + + Pseudomonas aeruginosa  + + + + + Haemophilus influenzae  + + + + + Escherichia coli + + + + + Vibrio cholerae  ...
+ + + + + Helicobacter pylori + + + + + Campylobacter jejuni + + + + + Erwinia carotovora + + + + + Yersinia pestis  + + +...
Thank you… [email_address]
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Metabolomics for finding new drug targets

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Metabolomics and Discovery of Drugs

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  1. 1. Metabolomics and Drug Discovery © All rights reserved P. Paulsharma Chakravarthy, School of Genomics, Loyola College www.milser.co.in [email_address]
  2. 2. Metabolomics….. <ul><li>Metabolomics is the study of metabolite profiles in biological samples, particularly urine, saliva and blood plasma; the total number of metabolites in the human is unknown: estimates range from 3000 to 30000 </li></ul><ul><li>The study of global metabolite profile in cells, tissues and organisms. The metabolite profiles are typically generated with high throughput NMR spectroscopy and mass spectroscopy </li></ul><ul><li>These profiles are represented by analytical spectra, the metabolite profiles of different cellular condition are compared using statistical techniques like pattern recognition </li></ul>
  3. 3. Metabolomics vs. other “omic” sciences <ul><li>Metabolite profile profiles provides knowledge and information rather than mere data </li></ul><ul><li>The genes and proteins predicts cell functioning but metabolites reflect actual cellular condition at the time of sampling </li></ul><ul><li>The sampling for the analysis is simpler compared to the genomics and proteomics </li></ul><ul><li>Can be used as Biomarkers for diagnostics and therapeutic monitoring </li></ul>
  4. 4. <ul><li>Metabolic profiling, the elucidation of the small molecule components of a cell, tissue or organism, has emerged as a useful technique in such diverse fields as drug discovery, clinical diagnostics and plant biochemistry </li></ul><ul><li>Metabolome is a pattern of molecules that reflects the cell’s status. It is the totality of metabolic processes including anabolism and catabolism, as well as all the related cellular processes such as absorption, distribution, and detoxification of natural and xenobiotic materials, energy utilization, signal transduction, and regulation. </li></ul><ul><li>It results from the expression of the genome and proteome in response to the cellular environment. While the Genome is representative of what might be, and the Proteome is what is expressed, it is the Metabolome that represents the current status of the cell or tissue . </li></ul>Metabolomics – Field Scenario
  5. 5. <ul><li>The Metabolome gives a direct picture of the cells activity and its environment. It presents a powerful portrait, reflecting health, disease, aging and the effects of drugs and the environment. </li></ul><ul><li>One method for extracting information is to separate and quantify the compounds of the Metabolome </li></ul>
  6. 6. Future Perspectives <ul><li>Detection of unusual metabolitic profile will aid in early cancer detection </li></ul><ul><li>Need for more public databases for Metabolomics research </li></ul><ul><li>Linking the metabolite datasets to genomics and proteomics </li></ul>
  7. 7. Metabolism Basics….. <ul><li>Definition - Metabolic pathways </li></ul><ul><li>Is a series of consecutive enzymatic reactions that produce specific products </li></ul><ul><li>Their reactants, intermediates and products are referred to as metabolites. </li></ul><ul><li>Basic concepts of Metabolic pathways </li></ul><ul><li>Metabolic pathways are irreversible </li></ul><ul><li>Every pathway has a first committed step </li></ul><ul><li>All metabolic pathways are regulated </li></ul><ul><li>Metabolic pathways in Eukaryotic cells occur in specific cellular locations </li></ul>
  8. 8. Study of Metabolome - In terms of sequence of reactions by which a specific nutrients is converted to end products, and the energetics of these reaction. - In terms of the mechanisms by which each intermediate is converted to its successor. Such an analysis requires the isolation and characterization of the specific enzymes that catalyze the reactions - In terms of the control mechanisms that regulate the flow of metabolites through the pathway.
  9. 9. <ul><li>Metabolic Inhibitors, growth studies and Biochemical Genetics </li></ul><ul><li>Isotopes in Biochemistry </li></ul><ul><li>Isolated Organs, cells and sub cellular organelles. </li></ul>Experimental Approaches Experimental approaches
  10. 10. Metabolic Pathway Databases
  11. 11. Representation of Pathways…
  12. 12. Gene Information - KEGG
  13. 13. Genome Map Representation - KEGG
  14. 14. <ul><ul><ul><ul><ul><li>Pathway Assist </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Transpath </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Genmapp </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Pathmetrics </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Metacore </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Pmap </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Pathway Editor </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Slirpp </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Pathway Analysis </li></ul></ul></ul></ul></ul>Metabolic pathway Mapping Tools
  15. 15. Practical Approaches <ul><li>Unique Biomolecules </li></ul><ul><li>Biosynthetic Pathway Targets </li></ul>
  16. 16. A Practical Example - Mycobacterium tuberculosis H37Rv <ul><li>Pathogenesis Process </li></ul><ul><li>Cell Wall Confers The Virulence </li></ul><ul><li>Biosynthetic Pathway of Cell wall Components as Potential Drug Targets </li></ul>
  17. 17. <ul><li>If only one enzyme-encoding gene out of a pathway of several steps is found in an annotated genome, it is likely to be a mistaken assignment. </li></ul><ul><li>Conversely, if all but one or two enzymes in a pathway have corresponding genes in the annotated genome, the missing steps are likely to be present amongst the unidentified genes and are worth hunting down. </li></ul><ul><li>Studying the metabolism of disease-causing organisms can also be an excellent means of identifying new drug targets. </li></ul><ul><li>Many pathogenic bacteria and parasitic eukaryotes are the subjects of ongoing genome sequencing projects. </li></ul><ul><li>If metabolic pathways can be identified which are essential in the pathogen but absent in the host, new drugs targeting the enzymes in these pathways are likely to be very effective. </li></ul>Applications of In Silico Mapping
  18. 18. Isoprenoids
  19. 19. Screening for Drug Target Pathways
  20. 20. DOXP and Mevalonate Pathway
  21. 21. Screening for Drug Target Pathways
  22. 22. + + + + + Pseudomonas aeruginosa + + + + + Haemophilus influenzae + + + + + Escherichia coli + + + + + Vibrio cholerae + + + + + Bordetella bronchisceptica + + + + + Bordetella pertussis + + + + + Neisseria meningitidis + + + + + Caulobacter crescentus + + + + + Rhodopseudomonas palustris Ych B Ygb B YgbP DXR DXS Organisms
  23. 23. + + + + + Helicobacter pylori + + + + + Campylobacter jejuni + + + + + Erwinia carotovora + + + + + Yersinia pestis + + + + + Pasteurella multocida + + + + + Salmonella typhimurium + + + + + Salmonella typhi -- -- -- + -- Pseudomonas fluorescens + + + + + Pseudomonas putida
  24. 24. Thank you… [email_address]
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