Integrated Chemical Workbench

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Integrated Chemical Workbench
A Reaction-Centered Synthesis Design Tool
Hartmut Braun Pharma Research Information
Management Hoffmann - La Roche Basel
Co-Developers Klaus Weymann Norman Nilsen,
MDL Tarkan Cevik, MDL
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Outline

• Concept - Reaction-Centered Approach
• The Workbench Application - Functionalities,
  Links, Databases
• Sample Session - Highlights
• Scope and Limitations of Synthetic Method
• Multistep Synthesis
• Reaction Control Options

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Concept
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Workbench and LabJournal Complementary Tasks
Workbench Virtual Synthesis design Generation
and evaluation of virtual drug candidates
LabJournal Real Synthesis execution (Robot
control) Synthesis documentation Storage of
patent-relevant data
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Workbench Application Areas

• Separation of
• library design and
• synthesis planning from synthesis execution
• provides flexibility to support
• Classical (sequential) medicinal chemistry
• Small-scale parallel synthesis
• Combinatorial Chemistry (HTC)

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Reaction-Centered Synthesis Design (1)
SSS in internal and external sources (ACD, RCI,
CIMS) Filters supplier, MW, quantity

Very large virtual library of thiazols 10000 -
1 million
Crude set of thiourea candidates 100 - 1000
Crude set of a-haloketone candidates 100 - 1000
X
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Reaction-Centered Synthesis Design (2)
ClogP, CpKa, toxicity, diversity, biol. tests
Validation of candidates Classification by FG
goodlist/badlist, diversity, price, toxicity,
purity Goal Candidate sets of manageable size
Medium to large virtual product library 100 -
10000
10 - 100
10 - 100
X
Virtual Screening Diversity Analysis
Novelty patent check CAS, Beilstein, ACD, RCI,
etc.
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Reaction-Centered Synthesis Design (3)
Medium to large product library 100 - 10000
10 - 100
10 - 100
X
Evaluation of reactions analogy, scope,
limitations Selection of educts for production
Small product sets 10 - 100
1 - 10
1 - 10
X
Substance ordering
Lab Journal
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The Workbench Application
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Tasks and Links

• Chemical Workbench
• Specification of synthetic method
• Data management
• Educts, products, reactions, associated data
• Searching, loading, sorting, classification,
  selection, deletion, scanning, printing, import,
  export

Search for educt candidates
Generation of products
Novelty check of products
ClogP
Diversity Analysis
Virtual Screening
Electronic Lab Journal
Excel
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Substructure Search for Educt Candidates and
Novelty Check of Products
NC, on the fly
NC, on demand
Other Public 18 million
SSS
RCI 700000 ROSA 120000 samples
Beilstein Handbook 1.2 million
HTC 100000
ACD 250000
CIMS 12000
External
Internal
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Sample Session
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Workbench Workflow
Define generic reaction
Generate virtual library
Evaluate products and specific reactions
Search and load educts
Evaluate educts
Select reactions for synthesis
Select building blocks for virtual library
Export reactions to Lab Journal
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Specification of Generic Reaction
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Scope and Limitations of Generic Reaction
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Scope Limitations of Generic ReactionUsing
Isis/Draw

• Standard substructure queries of educt and
  product components
• Connectivity, size
• Atom and bond query features
• Explicit H
• Atom/atom mapping
• Isis/Draw functionalities
• Are simple enough
• Are sufficient for the time being
• Advanced discrimination tools might be needed in
  the future

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Atom/Atom Mapping of Generic Reaction

• Determines how the Reactor transforms educts into
  products
• Creation, modification and deletion of atoms and
  bonds
• Manual assignment
• Safe
• Flexible
• Straightforward in most cases
• Isis AutoMap Rxn function
• Experimental
• Rules largely unknown

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Scope and Limitations of Generic Reaction Atom
Query Features

• Atom type, isotope, charge, radical
• A (any atom except H),
• Q (any atom except C or H)
• List, e.g. Cl, Br
• Not List (be careful)
• Substitution count
• Explicit H determines min. H count at atom

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Scope and Limitations of Generic Reaction Bond
Query Features

• Single, double, triple
• Aromatic
• Single/double
• Single/aromatic
• Double/aromatic
• Any

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Generic Reaction Stored in Workbench
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Searching Educt Candidates in ACD

• Filters
• MW
• Fluka, Merck, Aldrich
• Full range of search options available in ACD
  window

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Searching Educt Candidates in RCI/ROSA

• Filters
• MW
• Minimum amount
• Full range of search options available in
  RCI/ROSA window

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Evaluating Educts A
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Evaluating Educts B
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Generating Virtual Library
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Evaluating Products and Specific Reactions
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Exporting Reactions to Lab Journal
Exporting Reactions to Lab Journal
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Reactions Stored in Lab Journal
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Multistep Synthesis
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Multistep Synthesis

• Products of reaction step N may be used as educts
  for step N1
• New educts may be imported from the LabJournal
• Intermediate storage in local SD file

A B ? C
Lab Journal
SD file
C D ? E
SD file
E F ? G
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Multistep Synthesis (2)
Comprehensive Method
If intermediates of reaction sequence are
irrelevant then specify one comprehensive generic
reaction
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Reactor Control Options
- Suppress Intramolecular Reaction - Prevent
Cross Matching - Discard Orphan Product
Fragments
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Suppress Intramolecular Reaction
Off 3 products, reaction ambiguous On 2
intramolecular products suppressed, reaction
unique
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Prevent Cross Matching
Option Exclusive substructure matching A ? Educt
1 B ? Educt 2
Off - 3 products - rxn ambiguous On - 1
product - rxn unique
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Discard Orphan Product Fragments
Option allows to automatically discard irrelevant
product fragments like protecting groups or ester
components
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Thank you for your attention