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Tautomers - Advanced Databases for
in-silico Screening
Frank Oellien, Rhein-Main-Docking Meeting 2003
Overview
• Motivation
• Technical Aspects
• Rules and Examples
• Results (Database Size and Benchmarks)
• Workflow
• Summa...
Motivation I
• Tautomeric states can be relevant for biological
interactions
• Brandstetter et al., MMP-8-Inhibitors
J. Bi...
Motivation II
Tautomer Generation Applications (state of the art)
• Agent 2.0 (ETH)
• OEChem (OpenEyes)
• StereoPlex (Trip...
Technical Aspects (CACTVS) I
• Flexible, modular chemical data management
system
• C core library, Tcl command layer
• Mai...
Technical Aspects (CACTVS) II
Pre-defined Function with 18 tautomer
transformations: make_tautoset
loop input_file {
outpu...
Rules I
18 Pre-defined Tautomer Rules
• simple enol/keto exchange, long-range enol/keto
exchanges (including S, Se and Te ...
Rules II
• ketene/ynol exchange (including S, Se and Te
[O,S,Se,Te]
[O,S,Se,Te]
analogues)
H
• nitro/acid transform with i...
Examples
Database Expansion
800000
700000
600000
500000
400000

x
3,1

300000

x
3,6

200000
100000
0

x
2,5
Maybridge

x
3,2

x
2,...
Benchmarks
Platform: SGI Fuel R1400 / 600 MHz, 1 GB RAM
Performance depends on
• nature of the compounds
• number of tauto...
Virtual Screening Workflow @ Intervet
2D / 3D
Structure DB
(MDL)

PreProcessing

Tautomer
Generation

Specific 3D
Database...
Summary
Outcome
• flexible structure processing capabilities
• easy modifications of generator rules via scripting
• platf...
Future Tasks
• evaluate hit-retrieval within tautomer databases
for different ligand / protein complexes
• full integratio...
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Tautomers - Advanced Databases for in-silico Screening

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Rhein-Main-Docking Meeting 2003

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Transcript of "Tautomers - Advanced Databases for in-silico Screening"

  1. 1. Tautomers - Advanced Databases for in-silico Screening Frank Oellien, Rhein-Main-Docking Meeting 2003
  2. 2. Overview • Motivation • Technical Aspects • Rules and Examples • Results (Database Size and Benchmarks) • Workflow • Summary and Future Tasks
  3. 3. Motivation I • Tautomeric states can be relevant for biological interactions • Brandstetter et al., MMP-8-Inhibitors J. Biol. Chem. 276, 2001, 17405-12. • Pospisil et al., Ligands of Herpesviral Thymidine kinases, Helvet. Chim. Acta 85, 2002, 3237-50. • Software for Virtual Screening or docking adresses: • conformations • ionization states • stereo centers • tautomers    X
  4. 4. Motivation II Tautomer Generation Applications (state of the art) • Agent 2.0 (ETH) • OEChem (OpenEyes) • StereoPlex (Tripos) • no extensions by the means of user-defined rules • no tautomer-sensitive duplicate check Aim: Easily extensible and scriptable software that allows the integration and automation of tautomer generation in our existing screening workflow.  CACTVS: Chemical data management system
  5. 5. Technical Aspects (CACTVS) I • Flexible, modular chemical data management system • C core library, Tcl command layer • Main command: ens transform $eh $tlist <direction> <reactionmode> <flags> <overlapmode> <excludelist> <maxtautomers> <timeout> tlist: Transformation definition (SMIRKS line notation, Daylight) [#1:1][O:2][C:3]#[N:4]>>[O:2]=[C:3]=[N:4][#1:1] H N O H N O
  6. 6. Technical Aspects (CACTVS) II Pre-defined Function with 18 tautomer transformations: make_tautoset loop input_file { output = make_tautoset molecule_record loop output { write to output_file } } • combination of all tautomer transformation rules • tautomer-sensitive duplicate check • optional: output of most reasonable tautomer
  7. 7. Rules I 18 Pre-defined Tautomer Rules • simple enol/keto exchange, long-range enol/keto exchanges (including S, Se and Te analogues) • simple imine transforms • aromatic heteroatom H shift, long-range aromatic H H heteroatom aromatic shift N N O O • heteroatom hydrogen exchange, long-range hetero atom hydrogen exchange (heteroatoms: N, O, S, Se and Te) [N,S,Se,O,Te] [N,S,Se,O,Te] [N,C] [N,C] H [N,S,Se,O,Te] H [N,C] [N,S,Se,O,Te] [N,C]
  8. 8. Rules II • ketene/ynol exchange (including S, Se and Te [O,S,Se,Te] [O,S,Se,Te] analogues) H • nitro/acid transform with ionic or pentavalent nitro group • cyanuric acid transform • formamidinsulfonic acid transform (including N, Se and Te analogues) • HCN transform • phosphonic acid transform
  9. 9. Examples
  10. 10. Database Expansion 800000 700000 600000 500000 400000 x 3,1 300000 x 3,6 200000 100000 0 x 2,5 Maybridge x 3,2 x 2,2 Tripos Specs TimTec VitasM
  11. 11. Benchmarks Platform: SGI Fuel R1400 / 600 MHz, 1 GB RAM Performance depends on • nature of the compounds • number of tautomers SupplierDB Compounds/min Multiplier Maybridge Screening > 150 2,5 Asinex Platinum > 250 2,9 VitasM (in-hose Stock) > 560 3 Tripos Leadscreen > 1400 2,2
  12. 12. Virtual Screening Workflow @ Intervet 2D / 3D Structure DB (MDL) PreProcessing Tautomer Generation Specific 3D Databases (Catalyst, Unity) Tautomer-sensitive Duplicate check Data Analysis Virtual Screening
  13. 13. Summary Outcome • flexible structure processing capabilities • easy modifications of generator rules via scripting • platform independence protects long-term usability and investment • automation and implementation in existing workflow • Technical Limitations • constraints for experimentally known preferences of tautomeric states by means of simple rile-based estimations (no energetic estimations) • separate structure for each tautomer is needed for 3rd party databases
  14. 14. Future Tasks • evaluate hit-retrieval within tautomer databases for different ligand / protein complexes • full integration and automation of the application into in-house virtual screening workflow • coping with data increase • additional sets of scripts for ionization states and stereoisomerism
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