Chem. Prot: A Disease Chemical Biology Database Sonny Kim Nielsen – Ph. D student Computational Chemical Biology - CBS Department of Systems Biology - DTU sonny@cbs. dtu. dk Translational Informatics, january 2011
PLAN Drug-Target interactions and Target-Disease associations Chemical Biology repository (Chem. Prot) Biological Network and visualisation using Cytoscape
We hope for a simple concept… Drug Gene Phenotype
But in reality it is not so simple Phenotype Gene Phenotype Drug Gene Phenotype
What is the number of targets for a drug? 4400 drugs, 2. 7 targets/drug in average 1081 drugs, 5. 69 targets/ drug in average Wombat-PK
The pharmacology of a drug is still sparse Chemical similarity Compounds Proteins Garcia-Serna R et al. Bioinformatics 2010 Keiser MJ et al. Nat. Biotech 2007
What about phenotypes? Protein-Protein interactions Network (PPI) disease Especially genetic disorders (color blindness, Huntington’s disease, Cystic fibrosis) disease Prader-Willi syndrome (7 genes) disease Cancer, diabetes, mental illness
A quality-controlled human protein interaction network Download and reformat PPI databases Trans organism ppi transferral Automated scoring of all interactions 500 000 interactions between 10, 300 human proteins Lage et al. Nat. Biotech 2007
Tissue-specific pathology and gene expression of human disease genes and complexes Lage K, et al. , PNAS, 52, 20870 -20875 (2008)
Integration of chemical space into biological space Chemical space Phenomeinteractome Chemical bioactivity Disease chemical biology network
Chem. Prot: a disease chemical biology database 700. 000 unique bioactive compounds for 30. 000 proteins MACCs and pharmacophore fingerprints computed Protein-Protein Interactions data integration** Structural similarity search 428000 PPIs Compound 1 Compound 2 D 2 P 1 Disease-protein complexes D 1 P 2 Protein 1 Protein 2 OMIM, AKS 2, GO, Tissue specificity Taboureau O et al. 2011 Nucleic Acids Res.
An example with citalopram (antidepressant) Drug Bank Chembl 7 proteins Chem. Prot PPIs 49 proteins disease 629 genes forming 4141 interactions
An example with citalopram: Genes enrichment GO - cell communication (p-value 1. 32 e-86) - signal transduction (p-value 4. 07 e-81) OMIM - Major Depressive Disorder (p-value 3. 77 e-06) TPH 2; FKBP 5; HTR 2 A - Obsessive-Compulsive Disorder 1 (p-value 1. 67 e-04) HTR 2 A; SLC 6 A 4 AKS 2 - Schizophrenia 9. 02 e-24 - Bipolar disorder 6. 92 e-21 - Anorexia nervosa 6. 61 e-10 - Bulimia nervosa 1. 41 e-07 - Obesity 2. 20 e-05
An example with citalopram: Genes enrichment for DRD 4 Leukemia
An example with citalopram: Src regulation of h. ERG? Citalopram inhibits h. ERG (25 μM in Ch. EMBL) Associated to LQTS and arrhythmia
Future plan in Chem. Prot: Drugs categorization based on the Anatomical Therapeutic Chemical (ATC) Classification. In ATC classification system, the active substances are divided into different group according to the organ or system on which they act and their therapeutic, pharmacologcal and chemical properties
Drug – Target – Disease Classification through ATC Drugs categorization based on the Anatomical Therapeutic Classification (ATC)
Disease – Disease Network
Disease – Disease Network
Conclusion Systems chemical biology allow to investigate new direction in understanding molecular (adverse) effects of chemicals in biological systems.
Some technical information about biological network and Cytoscape.
Biological networks in Bioinformatics Graph theory Graph G=(V, E) is a set of vertices V (nodes) and edges E A subgraph G´of G is induced by some V´ V and E´ E Graph properties: - neighborhood - Connectivity (node degree, paths) - Directed vs. undirected Path theory A path is a sequence {X 1, X 2, …, Xn} such that (X 1, X 2), (X 2, X 3), …, (Xn-1, Xn) are edges of the graph. A closed path Xn= X 1 on a graph is called a graph cycle or circuit.
Biological networks in Bioinformatics Protein network representations
Biological networks in Bioinformatics Sparse vs dense
Clustering coefficient
How to represent interaction network? Network visualization and analysis tool. A community based framework for networks modeling www. cytoscape. org
Cytoscape Desktop Network Management panel Network overview panel Network graph and view Attribute browser
Input – output data Cytoscape reads an interaction network: – Using a interaction file (. sif, . txt, . csv…) – A XML format (essentially to store information and allows network data exchange with a variety of other network display programs A A B A D B B D C – Output can be a. sif format, txt, but also image (png, pdf, jpeg…) C C
Input – output data
Add information on nodes and edges
Visual style (Vizmapper) - Layout
Time for you to play And don’t stress…
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