The Bioinformatics of Small Molecules

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The Bioinformatics of Small Molecules

• David Wishart
• University of Alberta
• david.wishart_at_ualberta.ca

VanBUG Oct. 13, 2005
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25,000
metabolite
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Why Are Small Molecules Important?

• Constituents to all macromolecules (DNA, RNA,
  protein, carbohydrates)
• Serve as cofactors and signaling molecules to
  1000s of proteins
• The chemistry part of biochemistry
• 99 of all drug entities and 90 of all drug
  types are small molecules
• 90 of all biomarkers used in clinical chemistry
  are small molecules

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Small Molecules sit on top of the Pyramid of Life
Metabolomics Proteomics Genomics
1400 Chemicals
3000 Enzymes
25,000 Genes
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Molecular Informatics
Cheminformatics Bioinformatics Bioinformatics
1400 Chemicals
3000 Enzymes
25,000 Genes
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Cheminformatics vs. Bioinformatics

• Cheminformatics The application of information
  technology to the study, analysis, distribution
  and archiving of chemical data
• Bioinformatics The application of information
  technology to the study, analysis, distribution
  and archiving of molecular biological data

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Two Solitudes
Bioinformatics
Cheminformatics
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Cheminformatics vs. Bioinformatics

• Established in the 1960s
• Designed for the needs of organic chemists
• User-pay, limited public access
• Funded by large companies (MDL, Bielstein, Sigma,
  CAS)

• Established in the 1990s
• Designed for needs of molecular biologists
• Web-based, open access model
• Funded by large govt agencies (NCBI, EBI, NIH,
  GC)

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Blurring the Boarders
2000
2005
Meta bolomics
Systems Biology
Proteomics
Genomics
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Whats Driving This?
NIH Roadmap
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Whats Driving This?

• Govt funded drug discovery and drug research
• Drive to find newer and better clinical
  biomarkers
• Molecular imaging (fMRI, PET)
• Biosimulation and improved modeling of metabolic
  pathways
• Modeling past success of open data access model
  in biology to chemistry

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Major New Initiatives

• PubChem NIH/NCBI initiative
• BIND/SMID Genome Canada initiative
• KEGG Japanese initiative
• ChEBI European initiative
• DrugBank U of Alberta
• Human Metabolome Project - U of Alberta
• SimCell U of Alberta

Primary Focus on Databases
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PubChem
http//pubchem.ncbi.nlm.nih.gov/
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PubChem

• Released Sept. 16, 2004
• Part of the NIH Molecular Libraries Roadmap, led
  by Steve Bryant
• Contains more than 850,000 molecules
• 3 Linked databases Compound, Substance and
  Bioassay
• Links out to PubMed abstracts, NCBI 3D structures
  and other Entrez resources

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PubChem Details
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NIH vs ACS
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BIND Small Molecules
www.bind.ca
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SMID Small Molecule Interaction Database
http//smid.blueprint.org/
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BIND/SMID

• Shows links (and mol. contacts) between small
  molecules and the macromolecules to which they
  bind
• Extracted from PDB data
• Supports search by SMID ID, Protein GI, PDB ID,
  Domain ID, Taxonomy
• Supports BLAST sequence searches
• SMID Genomes lists putative ligand interactions
  based on SMID/SMID BLAST

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SMID Genomes
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KEGG Kyoto Encyclopedia of Genes and Genomes
http//www.genome.jp/kegg/
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KEGG

• First small molecule database, established in
  1996
• Links small molecules to EC data and known
  pathways
• Source data for many other small molecule
  databases and tools
• Provides limited linkage between small molecules
  and the enzymes they interact with

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KEGG Contents

• PATHWAY 29,921 pathways generated from 246
  reference pathways
• GENES 1,138,129 genes in 31 eukaryotes 241
  bacteria 24 archaea
• LIGAND 12,973 compounds, 2,469 drugs, 11,148
  glycans, 6,442 reactions
• BRITE 7,526 KO (KEGG Orthology) groups

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ChEBI Chemical Entities of Biological Interest
http//www.ebi.ac.uk/chebi/
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ChEBI

• Includes 5719 compounds and other molecular
  entities that are either products of nature or
  synthetic products used to intervene in the
  processes of living organisms
• Derived from KEGG Ligand, IntEnz and Chemical
  Ontology
• Provides structures, names, synonyms, InChI,
  Smiles, ontology, Registry s

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Major New Initiatives

• PubChem NIH/NCBI initiative
• BIND/SMID Genome Canada initiative
• KEGG Japanese initiative
• ChEBI European initiative
• DrugBank U of Alberta
• Human Metabolome Project - U of Alberta
• SimCell U of Alberta

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DrugBank
http//redpoll.pharmacy.ualberta.ca/drugbank/
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DrugBank

• A freely accessible, web-enabled, fully queryable
  database that links drug structure/activity data
  with protein structure/function/sequence data
• Brings well-developed bioinformatics concepts of
  search and comparison to medicinal chemistry
• Links bioinformatics, proteomics and drug
  discovery together

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DrugBank

• Contains nomenclature, synthesis,
  structure/activity, physical chemistry info on
  1000 FDA approved drugs
• Contains nomenclature, structure, sequence,
  pharmacology, drug metabolism info on
  corresponding biomolecular targets
• Wrapped with extensive querying and search tools

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DrugBank Browser
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DrugCard Links
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Query Tools
PharmaBrowse
ChemQuery
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Query Tools
SeqSearch
DataExtractor
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DrugBank Stats
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DrugBank Applications

• Newly sequenced proteomes can be analyzed
  automatically for similarities to existing drug
  targets, giving researchers quick lead ideas
• Newly determined protein structures can be
  Autodocked to a large 3D structure database of
  known, well-behaved compounds to suggest lead
  ideas

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DrugBank Applications

• Newly synthesized or identified lead compounds
  can be compared to existing structures to
  assess/predict possible efficacy, cross
  reactivity, metabolism or physical properties
• Existing drugs can be compared or analyzed for
  key trends, properties or features to help in
  drug design and drug synthesis efforts

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Major New Initiatives

• PubChem NIH/NCBI initiative
• BIND/SMID Genome Canada initiative
• KEGG Japanese initiative
• ChEBI European initiative
• DrugBank U of Alberta
• Human Metabolome Project - U of Alberta
• SimCell U of Alberta

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Human Metabolome Database
www.hmdb.ca
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HMDB

• A web-accessible database that links endogenous
  human metabolite data to genes and diseases
• Brings phys/chem data, structure data,
  spectroscopic data, concentration data, disease
  data and molecular biology data (SNPs, sequences,
  EC, GenBank, UniProt, GO, reactions, pathway,
  KEGG) into single repository

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The HMDB MetaboCard
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Major New Initiatives

• PubChem NIH/NCBI initiative
• BIND/SMID Genome Canada initiative
• KEGG Japanese initiative
• ChEBI European initiative
• DrugBank U of Alberta
• Human Metabolome Project - U of Alberta
• SimCell U of Alberta

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BiosimulationThree Types of Simulation
Atomic Scale 0.1 - 1.0 nm Coordinate data Dynamic
data 0.1 - 10 ns Molecular dynamics
Meso Scale 1.0 - 10 nm Interaction data Kon,
Koff, Kd 10 ns - 10 ms Mesodynamics
Continuum Model 10 - 100 nm Concentrations Diffusi
on rates 10 ms - 1000 s Fluid dynamics
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Nationalism in Simulation

• Petri Nets Germany, Japan
• Flux-Balance Analysis USA
• Pi Calculus France
• ODEs and PDEs Japan, UK
• Agent-Based methods (CA) - Canada

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CA Methods in Games
SimCity 2000
The SIMS
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Dynamic Cellular Automata

• A novel method to apply Brownian motion to
  objects in the Cellular Automata lattice (mimics
  collisions)
• Takes advantage of the scale-free nature of
  Brownian motion and the scale-free nature of
  heterogeneous mixtures to allow simulations to
  span many orders of time (nanosec to hours) and
  space (nanometers to meters)

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SimCell
http//wishart.biology.ualberta.ca/SimCell/
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SimCell

• Java application that uses Dynamic Cellular
  Automata (DCA) to model motions, interactions,
  transport and transformations at the meso-scale
  (10-8 to 10-6 m)
• Uses a square, 2D lattice to model processes,
  lattice squares are equivalent to 3x3 nm regions
• Molecular objects are moved randomly and
  interactions determined according to a set of
  interaction rules that are only applied when
  objects are in contact (collision detection)

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Diffusion in Cytoplasm
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Enzyme-Substrate Progress Curves
Lactate Lo (1 e-kt)
Lactate Lo (1 e-kt)
pyruvate NADH ? lactate NAD
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The TCA Cycle SimCell
Acetate
Acetyl-CoA
Glycerol
Pyruvate
Oxaloacetate
Citrate
Isocitrate
L-Malate
?-Ketoglutarate
Fumarate
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Succinate dehydrogenase
Succinate
Succinyl-CoA
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Succinate Production
Observed Predicted (SimCell)
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Glycerol Consumption
Observed Predicted (SimCell)
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Summary

• Small molecules are an integral part of genomics,
  proteomics system biology
• Several drivers are pushing or merging
  cheminformatics into bioinformatics
• New databases and new techniques are emerging to
  assist in drug discovery, toxicology, biomarker
  ID, cellular metabolism and cellular modelling
• Bioinformatics ? Biosimulation

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Thanks

• Craig Knox
• Savita Shrivastava
• An Chi Guo
• Murtaza Hassanali
• Zhan Chang
• Jennifer Woolsey
• Kevin Jewell
• Dan Tzur
• Kevin Jeroncic

• Joey Cruz
• David Arndt
• David Block
• Peter Tang
• Russ Greiner

AICML
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BioAssay Database

• The BioAssay Database contains bioactivity
  screens of chemical substances described in
  PubChem Substance
• Provides searchable descriptions of each
  bioassay, including descriptions of the
  conditions and readouts specific to a screening
  protocol