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