Chalmers Med Chem Oct07

PubChem and Related Open Cheminformatic Resources: A Revolution in the Connectivity Between Medicinal Chemistry and Biology
Course in Advanced Medicinal Chemistry (KEN760) Lecture
Chalmers Technical University, Oct 2007
Chris Southan, ChrisDS Consulting, Göteborg
http://www.cdsouthan.info/CDS_proff.htm

Outline
The way it was
The revolution
PubChem aims and content
Making the chemistry and biology joins
Chemical systems biology
Drug Bank and Chem Spider
Wider implications

The Context
Medicinal chemistry provides a bridge between biology and chemistry by identifying compounds that produce biological effects
Historically, the goal has been to optimize therapeutic efficacy and avoid undesired biological effects i.e. develop new medicines
However, it is increasingly recognised that bioactive cpds can be part of the perturbation toolbox for the investigation of all types of biological processes
By advancing biological knowledge at both the molecular and systems level such investigations can lead to improved understanding of disease and new opportunities for classical medicinal chemistry

Acceleration of Global Medicinal Chemistry Output
This includes not only ~ 30K development cpds produced over the last 20 years but also post-genomic, post-HTS, post-libraries output acceleration
Much of this is being published in med chem journals and estimates suggest global pharma/biotech patent output of at least 300K compound claims per year
Because the targetome is small we are approaching the point where nearly all tractable targets, directly or by homology, will have available chemical modulation starting points

The Conceptual Union Between Chemistry and Biology goes back a long way ….

So does Bioactive Compound Structure Representation…..

But Times Have Changed …..

November 2004: The Seeds of Revolution

Strophanthidin: from 1952 to 2007: Now just a click to Hinxton… http://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:38178

Or Bethesda…. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6185

PubChem and ChEBI: Revolutionary Consequences
Arrival of the ”missing entity” of formal and linked chemical structure representation within the global web of bioinformatic relationships

Ability to search across links between biochemical data, biological effects and chemical structure information

Deposition not just of HTS results but a wide range of other types of screening data directly linked to chemical structure information in public repositories

Proliferation of cheminformatics tools, databases, nomenclatures, and ontologies in the public domain

Proliferation of cheminformatics tools, databases, nomenclatures, and ontologies in the public domain
A quantum jump in the global enablement of chemical biology and medicinal chemistry

The NIH Roadmap Chemical Diversity Technology Development Screening Instrumentation Assay Development Predictive ADMET Compound Repository (MLSMR) Informatics Chem- informatics Research Centers Molecular Libraries Screening Centers Network ( M L S C N )

PubChem
PubChem is the NCBI informatics backbone for the NIH Molecular Libraries Initiative
A suite of three databases, PubChem Compound unique structures with computed properties ) PubChem BioAssay ( results supplied by depositors) and PubChem Substance ( deposited compound structures)
The ten MLI-funded screening centers are run cellular and target-based HTS’s using a compound collection of <140K and submitting the results to PubChem

Growth In PubChem Substances & Compounds Todays compound count: All: 10954831 BioAssay: 561883 Protein3D: 11717 Rule of 5: 7133978

GenBank PubChem

Top PubChem Depositors 56 current depositors 22 current depositors DiscoveryGate 4608994 ZINC 3813892 ChemDB 3564938 Thomson Pharma 2303628 ChemBridge 433971 ChemBank 413586 ChemIDplus 383789 Asinex 362469 DTP/NCI 268696 Specs 204658 DTP/NCI 173 NIH Chemical Genomics Center 60 Structural Genomics Consortium - Oxford 43 Scripps Research Institute 37 University of Pittsburg MLSC 33 Southern Research MLSC 29 San Diego Center for Chemical Genomics 22 BindingDB 20 Penn Center for Molecular Discovery 19 Emory MLSC; Vanderbilt MLSC 15

Growth In PubChem BioAssays Todays count: All: 637 Confirmatory: 250 MLSCN: 365 Protein Target: 257 Screening: 204 Summary: 1

PubChem Chemical Searching

Assay Example

Advanced Functionality

Bio-Chem Data Joins

The Biology Union

Entrez Connectivity Map

Expanding Relationships in Entrez Protein Sequences Literature PubMed VAST Structure Similarity Bioactivity Assay Results Small Molecule Structures Protein 3D Structures Biological Terms MeSH indexed 2D Chemical Structure Similarity (3D soon) Activity Profile Similarity Protein Sequence BLAST Sequence Similarity

A Pharmaceutical Portfolio from PubChem arixtra = CID 636380 factor Xa inhibitor odiparcil = CID 216385 thrombin inhibitor carvedilol = CID 2585 alpha/beta blocker levitra = CID 110634 PDE-5 inhibitor avodart = CID 152945 5-ARI inhibitor cutivate = CID 444036 anti-inflammatory hycamtin = CID 60699 topoisomerase inhibitor zofran = CID 4595 serotonin type 3 receptor antagonist avandir = CID 77998 PPAR gamma inhibitor seroxat = CID 5284605 SSRI wellbutrin = CID 62884 dopamine uptake blocker imigran = CID 5358 serotonin 5HT1 agonist lamictal = CID 3878 calcium channel blocker flixonase = CID 444036 anti-inflamatory serevent = CID 5152 adrenergic beta-agonist ariflo = CID 151170 PDE IV inhibitor SB 204070A= CID 121880 5-HT4 receptor antagonist SB-220453 = tonerbasat = CID 3055165 anticonvulsant

Joining to Protein Structure Cn3D view of PDB 1I7G on the left PubChem tesaglitazar=CID 208901 on the right Superimposed non-identical structural neighbours of 1I7G on the left with 90% similar neighbours of tesaglitazar=CID 208901 on the right.

Systems Chemical Biology
Oprea et al. Nat Chem Biol . 2007 (8): 447-50 PMID: 17637771
“ The increasing availability of data related to genes, proteins and their modulation by small molecules has provided a vast amount of biological information leading to the emergence of systems biology and the broad use of simulation tools for data analysis. However, there is a critical need to develop cheminformatics tools that can integrate chemical knowledge with these biological databases and simulation approaches, with the goal of creating systems chemical biology.”

Zebrafish Example

Public and Commercial Pathway Info

PubChem is now a Global Hub Including bioinformatic dbs with in-links ChemBank, chemical genomics 0.4 mill ChEBi, enzyme ligands 8K KEGG, drugs and metabolites 14K ZINC, ready-to-dock 3.8 mill MMDB, PDB ligands 55K ChemIDplus, NIH tox data 383K GPCR-Ligand Database Human Metabolite db 2K MEROPS protease inhibitors DrugBank, drugs and targets 4K P u b C h e m ChemSpider 20 million Nature Chemical Biology 0.8 K Drugs of the Future 3.4K LIPID MAPS, metabolism 8.8K

Relationships in Bioactive Chemical Space Protein Sequences metabolomes & natural products assay data drug-like cpds from literature & patents drugs chem genomics & sys biol probes

The Crucial Value of Explicit Compound-to-sequence Links
Increasing availability of extracted/curated/annotated relationships:
… document (or database entry) “V “ includes assay data “W” that defines compound “X” as an activity modulator of protein “Y” with sequence “Z”….
~ 130,000 cpds, ~1,300 sequences, ~7,000 papers
~ 2 million cpds ~ 5,000 sequences ~ 80,000 patents and papers
~ 4,000 cpds, ~ 6000 sequences

Complexities of Establishing Compound-to-sequence Links
Definitions, thermodynamic, enzymological, receptor pharmacology, what is a “target”, ect
The necessity for quantitative data from defined biochemical assays
Constitutive problems of extracting unstructured document data into relational database schema
Inherent biases of cross-screening data
Lack of assay standards or ontologies
Mapping between assay descriptions, gene names, symbols, sequence identifiers and primary structure isoforms
Establishing triage rules to encompass different degrees of ambiguity from source data
Blending automated extraction with expert annotation
Filtering and combining complex Entrez queries with PubChem intersects
Fundamental challenge of relating in-vitro activities of cpds to in-vivo pharmacology and clinical effects

Mapping the “Targetome”
Basal (unspliced) human proteome ~ 20,000
Extrapolated maximal “druggable”, targetome (H&G) ~ 3,000
Estimate of maximal tractable therapeutic targets (H&G) ~ 600 – 1,200
Targets with chemical starting points (GVKBIO all) 5595
Targets & pathways (Prous Integrity) 1866
Targets (WOMBAT 2006.1) = 1,320
PubChem Compound-to-RefSeq = 1081
Targets with chemical starting points (GVKBIO human) 1248
Therapeutic Targets Database = 997
Targets with <10 uM cpds (Paolini et al . human) = 836
Targets with <100nm Lipinski-compliant cpds (Paolini et al . human) = 529
Swiss-Prot - > DrugBank links (all) = 503
Big pharma project portfolio (Pfizer) = 479
Swiss-Prot - > DrugBank links (human) = 411
Targets marketed drugs (all) = 248 proteins,
Targets marketed drugs (human) = 207
Targets for marketed oral drugs (human) = 185

The DrugBank Data Extractor: Extensive Target-Cpd Joins

Linkage between Swiss-Prot - DrugBank - PubChem - MMDB see these marketed target links (411) (15728) = 181 (2501)

Commercial Products Complement Public Sources

Post-filtration Compound Counts (Oct 2006)
GVKBio 1,488,288
GVKBio Journals 542,858
GVKBio Patents 1,034,548
GVKBio Drug 1,933
WOMBAT 128,120
PubChem 7,268,193
PubChem Prous 3,318
PubChem PDB 5,626
PubChem actives 35,671
PubChem pharmacol 6,070
Bioprint 2,437
ZINC FDA 1,200
DrugBank 3,723
DrugBank small mol 1,018
DrugBank exp drugs 2,737
Dict. Nat.Prod. 132,831
MDDR 159,867
MDDR launched 1,118
CMC 8,189

PubChem and Commercial Target db Overlaps 7.27 mill 128K 1.49 mill PubChem GVKBIO 4,150 86,143 34,674 353,623 3,162 WOMBAT 1,013,848 6,825,265

Bio-Chem Connectivity not yet Completely Effortless
Relatively few specific target assays
The MLSC screening collection is modest
As a consequence of being “submitter-friendly” the NCBI cannot enforce stringent data standards
The “vendor-push” effect dilutes out actives
Valuble bioactivity dbs not yet reciprocally linked or Entrez-selectable
Explicit protein<->compound links not extensive
Caveats for raw HTS data
MeSH linking from the medicinal chemistry literature is thin
Limited public back-fill of compound-biology-sequence links from literature
Lack of an assay ontology
Entrez is massive and not for the faint hearted
Conceptual challenges of traversing chemistry<>bioinformatics<>protein structure >biology

Implications of Open Chemistry (I)
CAS tried to strangle PubChem (see Wikepedia PubChem entry)
At least in part, the NIH MLI was a response to the post-genomic productivity decline of pharma
It will enable drug research for orphan and tropical diseases that pharma could not take on alone
But progressing to clinical candidates will be challenging
Impact of commercial medicinal chemistry patent claims on public research is unclear
Impact of academic medicinal chemistry patent claims on commercial research is unclear
Pharma encouragement for more pre-competive collaboration
Collective responsibility for correct and standardised chemical structure representation
Controversy over open acess Chem-Bio journals and data links vs traditional publishing
Credibility issues e.g. PubChem-FDA-DrugBank-Wikepia

Implications of Open Chemistry (II)
Commercial monopolies on chemical information brokerage have cracked
But their opportunties have expanded in target annotation and pathway mapping
Benchmarking and standardisation opportunities from public HTS and other screening data
Academic opportunities for seaching patent cpds and data
More open-source cheminformatic tools will become available e.g. pharmacophore searching, virtual screening and docking
Academic experimental work may be limited by cpd availability
Will the revolution reach the patent offices and result in searchable e-submissions ?
While progess is being made in large-scale extraction and indexing of biological knowledge from the literature (conversion of unstructured to strucutred data) its not clear how the chemical literature will be back-filled
Increased collaboration and/or licencing opportunites for pharma and biotech

The New Literature Front-fill: Chemistry Central
Chemistry Central is a new open access website for chemists publishing peer-reviewed research in chemistry from a range of open access journals. The Chemistry Central Journal will cover all of chemistry and will be broken down into discipline-specific sections including Medicinal Chemistry will be a key discipline in this new journal.
Online publishing offers technologies not available in print-only format such as hyperlinking, video files, and interactive graphics and molecular superimpositions. Figures will be able to be submitted in ChemDraw (.CDX) or ISIS/Draw (.TGF) file formats. All articles will be deposited in PubMed Central, and will therefore be automatically linked into PubChem, based on the chemical substances that they mention. Additional information such as experimental or spectroscopic data can be linked electronically to structures within the document. The storage of supporting data should make this an invaluable SAR resource.

7-CHLORO-1-METHYL-5- PHENYL-2H-1,4- BENZODIAZEPIN-2-ONE SMILES strings: c1ccccc1 INChI=1/C6H6/c1-2-4-6-5-3-1/h1-6H Text Analysis Operations for Chemistry Documents: Backfilling from Patents and Papers Name  Structure Program language-free entities 6 6 0 0 0 0 0 0 0 0999 V2000 6.7092 5.6087 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 6.7076 4.5056 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 7.6607 3.9551 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 8.6160 4.5062 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 8.6121 5.6136 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 7.6583 6.1591 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0 0 0 0 2 3 1 0 0 0 0 3 4 2 0 0 0 0 4 5 1 0 0 0 0 5 6 2 0 0 0 0 6 1 1 0 0 0 0 M END Connection tables

The ChemSpider Mission
Build a structure centric community for chemists by:
Providing an environment for structure drawing, manipulation, visualization, modeling, databasing and searching
Providing methods by which to deposit, curate and enhance data associated with chemical structures
Providing structure-based access to federated Chemistry databases representing chemical vendors, literature, online data, patents and other forms of Chemistry data

Flexible Boolean Searching

Search result: 49 hits in 0.8 seconds

Integrated Visualization Tools

Integrated Analytical Data Management for Public Domain Data

Integrated Access to Open-Access Literature Text-based searching of over 50,000 Open Access Chemistry Articles

External Integrations - Google Search Across Google Using InChI string

External Integrations – Patents Reel Two Surechem Portal

Quality is a Major Issue
Pubchem structure-identifier pairs are proliferating
Care is needed or at least cleansing of the data

Acknowledgments
Colleagues from AstraZeneca Global Compound Sciences
Steve Bryant and the NCBI PubChem team
Chris Austen and the NIH Chemical Genomics Centre team
Antony Williams for ChemSpider slides

Chalmers Med Chem Oct07

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