The NIH Roadmap and PubChem

1
The NIH Roadmapand PubChem

• Gary Wiggins
• I533
• Spring 2006

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NIH Roadmap

• Series of initiatives designed to pursue major
  opportunities in biomedical research and gaps in
  current knowledge that cannot be addressed by any
  single NIH Institute or Center
• Goal enable rapid transformation of new
  scientific knowledge into tangible benefits for
  public health
• http//nihroadmap.nih.gov/

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NIH Molecular Libraries and Imaging Initiative

• Part of the New Pathways to Discovery area
• Goal augment the toolbox for understanding the
  functionally interconnected molecular events
  that maintain health and lead to disease
• Build on high-throughput, highly specific,
  mechanism-based biological assays
• Aims to develop and discover small molecules that
  hold promise as research tools to probe cellular
  physiology and pathophysiology

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NIH Molecular Imaging Roadmap

• High specificity/high sensitivity molecular
  imaging probes
• Molecular imaging and contrast database
• Imaging probe development center

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NIH Roadmap Molecular Libraries Initiative (MLI)

• A series of integrated research programs with the
  goal of making small molecule screening and
  screening data more widely available to the
  research community
• http//nihroadmap.nih.gov/molecularlibraries/index
  .asp

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MLI Aims

• Go beyond the identification of compounds with
  potential therapeutic properties
• Will result in the identification of compounds to
  use as probes to study cellular processes in
  health and disease
• Biological screening data, assay protocols, and
  chemical structures for compounds to be publicly
  available in PubChem

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NIH MLI Components

• Molecular Libraries Screening Center Network
  (MLSCN)
• Cheminformatics (centered around PubChem)
• Technology development

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NIH MLI Technology Development Areas

• Chemical diversity
• Pilot-scale libraries for investigation of novel
  chemical diversity space
• Novel methods for natural product chemistry
• Development of assays
• Novel instrumentation and detection technologies
  for high throughput screening
• Datasets and algorithms for better prediction of
  absorption, distribution, metabolism, excretion,
  and toxicity properties of small molecules

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Assay Guidance Manual

• Originally written as a guide for therapeutic
  projects teams within Eli Lilly covers
• Identifying potential assay formats compatible
  with High Throughput Screen (HTS) and Structure
  Activity Relationship (SAR)
• Developing optimal assay reagents
• Optimizing assay protocol with respect to
  sensitivity, dynamic range, signal intensity and
  stability
• Adaptation of the assay to the microtiter plate
  formats
• Validation of the assay performance
• Orthogonal follow-up assays for chemical probe
  validation and refinement
• http//www.ncgc.nih.gov/guidance/index.html

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NIH Molecular Libraries Small Molecule Repository

• Run under contract by Discovery Partners
  International
• Collects samples for high throughput biological
  screening and distributes them to the NIH
  Molecular Libraries Screening Center Network
• http//mlsmr.discoverypartners.com/MLSMR_HomePage/
  

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Roadmap MLI Funded Areas

• Molecular Libraries Screening Centers (MLSCN)
• Ten of them at academic institutions
• NIH Chemical Genomics Center
• http//www.ncgc.nih.gov/
• http//nihroadmap.nih.gov/molecularlibraries/funde
  dresearch.asp

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Roadmap MLI Funded Areas

• Submitting assays for HTS in the MLSCN
• 28 different submissions
• Pilot-scale libraries for HTS (8)
• New methodologies for natural product chemistry
  (6)
• Assay development for HT molecular Screening (39)
• Molecular libraries screening instrumentation (4)

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Roadmap MLI Funded Areas

• Novel preclinical tools for predictive
  ADME-Toxicology (5)
• Innovation in molecular imaging probes (11)
• Development of high-resolution probes for
  cellular imaging (9)

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Roadmap MLI Funded Areas

• Exploratory Centers for Cheminformatics Research
  at
• Indiana University
• University of Michigan
• Rensselaer Polytechnic Institute
• MIT
• North Carolina State University, Raleigh
• University of North Carolina, Chapel Hill

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IU Projects Underway

• Innovative cross-screen analysis of NIH
  Developmental Therapeutics Project Human Tumor
  Cell Line data
• Development of cheminformatics web services and
  use cases in Taverna
• Development of a novel interface for the analysis
  of PubChem HTS data
• A structure storage and searching system for
  Distributed Drug Discovery
• Quantum chemical computer simulations database
• Training modules for cheminformatics instruction
  on the Web
• Web guide for essential cheminformatics resources
  (http//www.indiana.edu/cheminfo/cicc/resources.h
  tml)
• Design of a grid-based distributed data
  architecture for chemistry

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NIH NCI Developmental Therapeutics Program

• The NCI has been collecting and testing compounds
  for 50 years. For about 30 years this has been
  managed by the Developmental Therapeutics Program
  (DTP). From 1955 to 1985 the primary test was to
  look for increase in survival of mice bearing
  transplantable tumors. In 1990, the primary
  screen switched to looking for inhibition of
  growth of 60 human tumor cell lines in culture.
  DTP also ran the anti-HIV screen for about 10
  years and managed the yeast anti-cancer screen in
  which compounds were tested for their ability to
  inhibit the growth of yeast strains with defined
  mutations in cell cycle genes. These assays
  provide the bulk of the data DTP makes publicly
  available.

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NIH NCI DTP

• DTPs correlation analyses allow one to associate
  a list of genes with a given compound or vice
  versa
• Want to get workflows running that integrate
  chemical structure data with the gene expression
  and sequence data in the bioinformatics world
• Need help in the practical details of creating
  web services that will work in the mygrid/Taverna
  (or equivalent) framework

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NIH DTP Data
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NCI Panel of 60 Human Cell Cancer Lines

• Protein levels
• RNA measurements
• Mutation status
• Enzyme activity levels

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NIH DTPs COMPARE Program

• The pattern of activity across all 60 cell lines
  that a compound exhibits is related to the
  mechanism of action
• Can be used to discover the mechanism of a
  compounds actions by looking at which compounds
  of known activity are correlated with the unknown
• Has been used to discover novel compounds with a
  given activity by testing the top correlating
  compounds to a compound with the activity of
  interest
• Used to prioritize compounds that seem to have a
  novel mechanism
• Calculates a correlation coefficient between two
  vectors in 60-dimensional space

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NIH DTP

• Given a compound tested in the 60 cell assay, one
  can look for the genes whose expression most
  highly correlates with the ability of the
  compound to inhibit cell growth. Conversely,
  given a gene, one can look for compounds whose
  ability to inhibit cell growth is most highly
  correlated with the expression of that gene.

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NIH DTP Needs

• Grid Web services
• Visualization may use VOTables
• Tools to squish a set of points in a large
  dimensional space down into 2D or 3D while
  attempting to preserve the relative distances
• Looking at the nearest neighbors of the point of
  interest with such a map could reveal relations
  that would be missed in just a table listed by
  distance

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NIH DTP Main Search Page

• http//dtp.nci.nih.gov/docs/dtp_search.html

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High-Throughput Screening (HTS)

• the integration of biological, chemical and
  clinical data
• automated standardized statistical analysis of
  large and complex data volumes
• biological and chemical profiling by use of
  statistical analyses on combined data from
  screening, pharmacological profiling, and
  structural properties

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Other Potential Partners

• Center for Chemical Genomics at the University of
  Michigan
• http//www.lifesciences.umich.edu/institute/labs/c
  cg/index.html
• Milos Novotny (IUB Chemistry) 3.5 million
  National Center for Research Resources (NIH)
  grant to conduct research in the analysis of
  glycoproteins
• David Flockhart (IUB School of Medicine)
  Cytochrome P450 database http//medicine.iupui.edu
  /flockhart/

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PubChem

• 5,298,729 compounds as of 1/16/2006
• the place to go for biological and related data
• the central depository of all information related
  to the NIH Roadmap project
• expected that the actual data will reside there,
  and only some things may be held elsewhere, with
  PubChem acting as a pointer
• May even have the images from screens and assays
• chemical structures from Elsevier's xPharm
  database

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PubChem Data (as of 10/25/2005)

• Bioassays deposited 177
• Bioassay test results 3,158,669
• Substances deposited 7,848,390
• Unique Substances 5,269,228

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PubChem Technical Details

• Entrez database system
• For all textual information in the database
• NCBI Toolkit - an open-source infrastructure
  toolkit
• OpenEye OEChem toolkit and associated software
• for most structure standardization tasks, plus
  some structure identifier computations like
  SMILES and IUPAC name generation.
• NIST InChI library
• for computing the InChI identifier
• CACTVS Chemoinformatics Toolkit
• for structure depictions, structure database
  system, structure query execution, structure
  deduplication, some property calculations and the
  WWW structure and image editors
• Various general low-level support libraries,
  e.g.,
• zlib, png, gd and freetype libraries
• In-house code
• for the queuing system, deposition system,
  display CGIs, structure standardization set-up,
  update scripts, etc.

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PubChem Database Display and Query Subsystems - 1

• A special Entrez version
• stores textual and numerical data
• hosted on a MS SQL Server relational database
  cluster
• holds precomputed structure images for display,
  ASN.1 structure data blobs for download, and
  extensive crosslinking functions for linking to
  other NCBI databases

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PubChem Display and Query Subsystems - 2

• structure search component
• based on the CACTVS structure search system
• pseudo-relational in nature (the underlying
  storage manager is the Sleepycat BDB database
  manager)
• hosted on a Linux server cluster
• structure search file is not stored in the SQL
  database, but there is an automatic
  synchronization and update mechanism
• Some data, such as Lipinski filter criteria, are
  stored in both databases

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PubChem Programming Utilities

• Entrez Programming Utilities
• http//eutils.ncbi.nlm.nih.gov/entrez/query/static
  /eutils_help.html
• CACTVS chemoinformatics toolkit
• a full ASN.1 parser for CACTVS understands the
  full data spec for structures and assay data
• modules for talking to the Entrez database for
  accessing structure blobs and some other NCBI
  systems

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PubChem Data Deposition

• PubChem Deposition Gateway
• http//pubchem.ncbi.nlm.nih.gov/deposit/deposit.cg
  i

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PubChem Sketcher

• No need to worry about the type of structure
  definition displayed in the top line
• uses a hidden internal representation to transfer
  the information
• http//pubchem.ncbi.nlm.nih.gov/search/

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InChI, The IUPAC International Chemical
Identifier

• Official site http//www.iupac.org/inchi/
• Unofficial InChI FAQ
• http//wwmm.ch.cam.ac.uk/inchifaq/
• WSDL InChI server at
• http//wwmm.ch.cam.ac.uk/gridsphere/gridsphere

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Searching InChIs

• Sample search
• InChI1/C17H14O4S/c1-22(19,20)14-9-7-12(8-10-14)1
  5-11-21-17(18)16(15)13-5-3-2-4-6-13/h2-10H,11H2,1H
  3
• Must include the quotation marks
• no carriage return or line feed in the string
• InChI code for C60 fullerene
• InChI1/C60/c1-2-5-6-3(1)8-12-10-4(1)9-11-7(2)17-2
  1-13(5)23-24-14(6)22-18(8)28-20(12)30-26-16(10)15(
  9)25-29-19(11)27(17)37-41-31(21)33(23)43-44-34(24)
  32(22)42-38(28)48-40(30)46-36(26)35(25)45-39(29)47
  (37)55-49(41)51(43)57-52(44)50(42)56(48)59-54(46)5
  3(45)58(55)60(57)59

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ACD Labs and InChIs

• Transferring structures from PubChem to
  ACD/ChemSketch
• http//www.acdlabs.com/download/technotes/90/draw_
  db/pubchem.pdf

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InChI Support in BKChem

• BKchem - a free chemical drawing program
• Successfully reads most InChIs
• http//bkchem.zirael.org/inchi_en.html

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InChI

• PubChem sketcher also supports generation of
  InChI strings
• http//pubchem.ncbi.nlm.nih.gov/edit/
• change the format selector to "InChI"

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Protein Data Bank (PDB) Data Dictionaries

• develop software and data definitions to support
  the structural genomics efforts
• enable high-throughput data deposition
• data dictionaries define items at the level of
  detail of the materials and methods section of a
  journal
• uses macromolecular Crystallographic Information
  File (mmCIF) data dictionaries
• http//mmcif.pdb.org/index.html

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Translate WSDL to Human Readable Form

• http//soapclient.com/soaptest.html