Accelrys Workshop, 30Sep 1Oct 2002

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Accelrys Workshop, 30-Sep / 1-Oct 2002

• ACE - Accord CombiChem Enhancement
• for Lead Generation
• Dr. Hartmut Braun
• Hoffmann - La Roche, Basel
• Pharma Discovery Chemistry
• Lead Generation

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Overview

• User requirements, project goals
• Integration into Roche environment
• HTC workflow
• Sample session
• Functionalities
• Accord Ace architecture
• Modules
• Techniques
• Proposals for improvement
• Summary, experiences

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Goals (1)

• Integration of Accord CombiChem into Roche
  environment
• Focus Basel Lead Generation
• Also Penzberg and Palo Alto
• Improvement of workflow for parallel synthesis in
  Lead Generation
• Design of combinatorial syntheses
• Support of chemical libraries with up to 2000
  compounds
• Management of lab data (prep. HPLC, etc.)
• Bulk substance registration in global Roche
  compound repository (IRCI)
• Link to Analytics (Arcade Analytics Submission
  Form Export of Molfiles for NMR)

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Goals (2)

• Transfer of essential functionalities from
  ChemBench and Workbench to Accord CombiChem
• Internal developments
• Unsupported
• Goal Removal
• Enhancement of Lab Notebook SOP to cover HTC
• Compliance with legal requirements
• Provision of global access to HTC knowledge
• Upload of reactions into Roche Reaction Database
• Task
• Design and implementation of safe, easy-to-use
  functionalities
• Based on Accord CombiChem
• Data management in Excel

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Integration into Roche Environment
IRCI
HPLC, MS Chromeleon
Accord CombiChem for Excel

• Data
• LabJ Ref
• ERN
• Prep Descr

Registration
Import, Selection
Ace Addin Enhancements for Lead
Generation
ERN from LabJ Ref

• Vocabularies
• Color
• Structure Cmnt

Data Validation
Rules
Export of Molfiles
Reactions
PhysChem Prop
Roche Reaction DB
Analytical data
From Isis LabJournal
NMR
LogP, pKa, Solubility, Rule of 5
From Ace Combi Workbook
Analytics
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New HTC Workflow Using Accord /Ace

• Design
• Definition of generic reaction with Rgroups
• Import of building blocks
• Clipping
• Definition of combinatorial LabJournal Reference
• Generation of products (library enumeration)
• Lab Work
• Synthesis
• Purification, Analysis, Validation
• Registration of products in IRCI
• Import of Roche Numbers (ERNs) from LabJ
  References

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Definition of Generic Reaction
Rules are simple, straightforward

• Generic reaction consists of scaffold and one or
  more Rgroups
• An R label specified on the left side of the
  arrow must also appear on the right side
• Separate the reactant and product components by a
  sign
• Use R1, R2, ... labels for the Rgroups
• An R label cannot be unattached, and it cannot be
  attached to another R label.

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Import and Clipping of Building Blocks

• Specify building blocks
• Via file import
• Via Isis/Draw
• Clip Reactants
• Clipping also possible with spiro or fused-ring
  compounds
• Add data columns like MW, MF, composition
• Calculate amounts of starting materials

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Failed or Ambiguous Clipping

• Failed Clipping
• A reactant whose clipping fails cannot react and
  will not yield a product in the enumeration
• Ambiguous Clipping
• Accord executes a reaction exhaustively
• A reactant that can react at multiple sites may
  yield ambiguous products
• Use the Edit Clip Choices command to discard the
  undesired alternatives

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Import of Building Blocks - Chiral Flagging
1. Enter Reactants 2. Clip Reactants

• Chirality of building block perceived by Accord
  CombiChem
• Chiral flag is assigned to clipped Rgroups

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Assigning Combinatorial LabJournal References

• Requirements
• Simple correlation with synthesis plate
• Unique correlation with ERN
• In principle Enumeration Options provide
  solution
• But Prefix - separator - suffix fields limited
  to 8 chars
• Workaround needed

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Roche-compliant Combinatorial LabJournal Ref
Reactant 1 (CLIPPED)
Reactant 2 (CLIPPED)
20034B012A01A
A, B, C for optional byproduct
LabJournal Number given to you by the Library
Services
Index A, B, C for BB 1
Page number in LabJournal. Constant for one
enumeration (batch)
Index 1, 2, 3 for BB 2
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Building Block Combinations and Synthesis Plate

• The Roche-compliant numbering allows you to
  easily correlate the LabJournal References with
  the synthesis plate
• 2-component reaction

A
B
C
1
2
3
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Enumeration and Chiral Flagging

• Product contains Chiral flag and correct stereo
  configuration according to building block(s)
• The LabJournal Ref is copied from the CHEMISTRY
  field

ACE creates mandatory fields and fields from
private template during Enumeration
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Purification and Analysis

• Compounds are purified by prep. HPLC
• Ace generates Purification Result sheet during
  Enumeration
• Chemists imports purification and analysis
  results (fraction and initial amount Chromeleon)
  into Purification Result sheet
• Chemist evaluates synthesized compounds
• Finally, the chemist transfers the purification
  results into the Enumeration sheet (next slide)

• Fields
• Export Flag
• LabJournal Ref
• Initial Amount
• MS Ref Number
• NMR Ref Number

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Importing Purification Results
Exportyes rows on the Purification Result sheet
are copied to the Enumeration sheet
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Adding Data Fields

• Ace supports more than 40 predefined IRCI fields
• Mandatory
• Optional (exported to IRCI if valid data exist,
  e.g. Color, Form, Preparation Description)
• Plus private fields

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Saving Workbook as Private Template

• Move field
• Save workbook as private template
• Name
• Sequence
• Hidden/visible
• Formulas
• Private template applied on Enumerate command
• Ace fills in default data

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Preparation Description for Each Product
Right mouse click
You can enter a detailed preparation description
for each product Description is fully integrated
in the workbook Description will be exported to
IRCI
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Selecting IRCI-compliant Terms From Vocabulary
Right mouse click on data cell displays vocabulary
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Setting Default Values
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Registration of Products in IRCI
Select the structures you wish to register
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Ace Connects to the IRCI Portal
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Retrieval of ERNs from IRCI
The Import ERNs command links to the IRCI
database and retrieves the ERN for all LabJ Refs
on the sheet
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Exporting Molfiles for Analytics (NMR)

• Each Molfile contains 1 product
• The file name is the LabJournal Reference , e.g.
  200123.mol
• Chemist submits files to NMR Service (together
  with Analytics Submission Form)

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Ace Architecture

• Ace addin programmed in Excel 97 (!) VBA
• To be migrated to XP in Q4.2002
• Enhanced functionality
• Improved robustness
• Better performance
• Enhanced Combi workbook template
• Event trapping (right mouse click, worksheet
  change). Requires caution.
• Ace addin loading and unloading
• Link to Oracle via ADO 2.5

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Accord CombiChem References

• Proposed enhancement
• Allow customers (developers) to add their own
  references to the CombiChem workbook template

Currently protected
Reference to Ace25.xla
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Ace Architecture

• Conclusion
• Accord CombiChem architecture reasonably open
• Allows the customer to add new functionalities
  through
• Excel addins
• CombiChem workbook extensions

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Summary

• Essential HTC functionalities (Ace 1.0) developed
  within 3 months in close collaboration with
  chemists and technicians
• HTC workflow now significantly easier, faster and
  safer
• Easy bulk registration of substances in IRCI
• All essential data in one Excel CombiWorkbook
• Generic reaction, building blocks, products,
  specific reactions, analytical and purification
  data, IRCI-mandatory data, IRCI-optional data,
  preparation description, LabJ Ref, ERN, private
  data
• Barcode label printing
• Ace User Guide
• Support and maintenance established
• Workbench and ChemBench removed
• Accord CombiChem Ace well accepted by users

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Proposed Accord CombiChem Enhancements

• Provide option to hide command panel
• More space for viewing structures and data
• Provided automatically with Office 2000
• Extend prefix - separator - suffix fields to 20
  chars
• Allow customer to add references to CombiWorkbook
  template

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Acknowledgement

• Chemistry
• M. Nettekoven, W. Haap, B. Puellmann, S. Schmitt,
  E. Bald, C. Dietrich, P. Hilti, S. Ohnmacht, R.
  Norcross, T. Luebbers
• Infrastructure
• D. Wechsler, P. Kallehave, D. Heinrich, M.
  Bartolotta
• Access to IRCI
• F. Agnetti, M. Assfalg, T. Black, J. Schmiedle,
  A. McTaggart, K. Weymann
• Sponsors
• A. Alanine, H. J. Boehm

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• Thank you for your attention