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Rhein-Main-Docking Meeting 2003
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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• Summary and Future Tasks
Motivation I
• Tautomeric states can be relevant for biological interactions
• Brandstetter et al., MMP-8-InhibitorsJ. 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
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 thatallows the integration and automation of tautomergeneration in our existing screening workflow.
CACTVS: Chemical data management system
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]
OH
N ONH
Technical Aspects (CACTVS) II
Pre-defined Function with 18 tautomer transformations: make_tautoset
loop input_file {output = make_tautoset molecule_recordloop output {
write to output_file}
}
• combination of all tautomer transformation rules• tautomer-sensitive duplicate check• optional: output of most reasonable tautomer
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
heteroatom aromatic shift
• heteroatom hydrogen exchange, long-range hetero atom hydrogen exchange (heteroatoms: N, O, S, Se and Te)
ON
HO
NH
[N,S,Se,O,Te]
[N,C] [N,C]
[N,S,Se,O,Te]
H
[N,S,Se,O,Te]
[N,C] [N,C]
[N,S,Se,O,Te]
H
Rules II
• ketene/ynol exchange (including S, Se and Te analogues)
• 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
[O,S,Se,Te] [O,S,Se,Te]H
Examples
Database Expansion
0
100000
200000
300000
400000
500000
600000
700000
800000
Maybridge Tripos Specs TimTec VitasM
x2,5
x2,2
x3,1
x3,6
x3,2
Benchmarks
Platform: SGI Fuel R1400 / 600 MHz, 1 GB RAM
Performance depends on• nature of the compounds• number of tautomers
SupplierDB Compounds/min MultiplierMaybridge Screening > 150 2,5Asinex Platinum > 250 2,9VitasM (in-hose Stock) > 560 3Tripos Leadscreen > 1400 2,2
Virtual Screening Workflow @ Intervet
2D / 3DStructure DB
(MDL)
Specific 3DDatabases
(Catalyst, Unity)
TautomerGeneration
Pre-Processing
Tautomer-sensitiveDuplicate check
Data Analysis Virtual
Screening
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
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