Fragment-based de novo Design

Transcription

1 ragment-based de novo Design Gisbert Schneider & Uli echner Beilstein Endowed Chair for Cheminformatics Institute of rganic Chemistry & Chemical Biology Johann Wolfgang Goethe-University rankfurt, Germany

2 avigation Is Defined As... "The process of determining and maintaining a course or trajectory to a goal location. (ranz & Mallot, Robot. Autonom. Syst. 2000, 30, 133)

3 What We eed for Exploration Coordinate system ( chemical space ) Guide through chemical space ( compass, map ) Target ( goal location ) Molecule generator ( vessel ) Each map has a certain resolution & meaning

4 De novo Design: Exploiting the Twilight Zone Library Diversity Scaffold-opping M.C. Escher s Regular Division of the Plane I SAR Information 1999 Cordon Art B.V. - Baarn - olland. All rights reserved.

5 ragment-based Design combinatorial optimization principle manageable size of search space might result in chemically feasible molecular designs side-chains and scaffolds are interchangeable Cl R 1 R 1 R 2 R 2 Traditional combinatorial thinking Scaffolds & side-chains ragment-based design nly building-blocks (fragments)

6 The Concept Drug DB RECAP ragment DB Reactions Reference Molecule(s) itness unctions Assemble (TPAS: lux-generator ) Designed Molecules RECAP: Lewell et al. (1998) J. Chem. Inf. Comput. Sci. 38:511 TPAS: Schneider et al. (2000) J. Comp. Aided Mol. Des. 14:487

7 RECAP Eleven Bond Cleavage Types Amide Ester Amine Urea + Ether lefin Quarternary Arom. aliph. C S Lactam aliph. C Arom. C arom. C Sulphonamide Lewell et al., JCICS 1998.

8 Reaction Amide Ester Amine Urea Ether lefin RECAP Applied to the CBRA Database Quart. itrogen Arom. Aliph. C Lactam Aliph. C Arom. C Arom. C Sulphonamide CBRA: Schneider & Schneider (2003) QSAR Comb. Sci. 22:713 Total ragments Unique ragments

9 TPAS II: The Implementation Start Generate λ diverse molecules 11 3,788 Reactions ragments #Atoms (!): #+# 12 Determine Quality (Daylight ingerprints & Tanimoto Coefficient) Generate λ molecules (mutation) Select best solution End Yes Stop? o

10 Daylight Toolkit unctions dt_fp_allocfp dt_fp_euclid dt_fp_tanimoto dt_smirkin dt_utransform dt_umatch dt_smartin dt_cansmiles dt_copy dt_dealloc dt_smilin dt_weight dt_getrole dt_stream dt_next allocate a new fingerprint compute the euclidean distance between two fingerprints compute the tanimoto coefficient of two fingerprints interpret a string as a generic reaction apply a reaction transform to an object match a pattern against an object interpret a SMARTS string retrieve the canonical SMILES string of an object make a copy of an object remove an object from the system interpret a SMILES string return the atomic weight of an atom get the role an object plays in a reaction allocate a stream object retrieve the next object in a compound object

11 SMIRKS/ ReactionSMILES for Virtual Synthesis Aromatic-C + Aromatic-C ([c;r1:1][10*]).([10*][c;r1:2])>>[c;r1:1]-[c;r1:2] Aromatic Reaction type & site index carbon Member of Atom mapping index exactly one ring [10*] + [10*]

12 The TPAS II lux-generator Parent Structure Child Structure Step 1 Step 3 Randomly select a reaction and retro-synthesize Amide Amide Synthesize with reaction chosen in Step ragmented Parent Structure Step 2 Randomly pick a fragment and substitute by a fragment of the 4/11/04, same type Cambridge, UK 2 ragmented Child Structure

13 Design Examples - apsagatran S apsagatran recapped CBRA Daylight ingerprints Tanimoto Coefficient non-adaptive EA 2 S T = 0.9 2

14 Design Examples - Gleevec Gleevec recapped CBRA Daylight ingerprints Tanimoto Coefficient non-adaptive ES T = 0.88 T = 0.87

15 Scaffold-opping & Combinatorial Design R CB-1 Seed (nm) (Khanolkar et al. 2000) C 2 Et R' R 2 De novo design ocused libraries R 1 R = ; Br; MeS2; GPCR-BB clogp = 6.90 clogp = 7.79 clogp = 5.47 DB 3 Rogers-Evans et al. (2004) QSAR Comb. Sci. 23:426 R'

16 Bioactivity of hcb-1 ocused Libraries R R 6% it Rate 10% it Rate R' R' R R IC 50 (hcb-1) / µmol * Cl 4.0 * tbu 4.0 R R IC 50 (hcb-1) / µmol 2,4-C Cl 3.0 * * * tbu 9.0 Cl 6.0 * Ph C 2 CC 3

17 Scaffold-opping: ovel Kv1.5 Blockers Schneider et al. (2000) Angew. Chemie Int. Ed. 39:4130 IC 50 < 1 µm (ICAGE) S De De novo Design S IC 50 < 1 µm S IC 50 ~ 7 µm PPP Matching S Virtual CombiChem IC 50 ~ 1 µm

18 Acknowledgements Evgeny Byvatov Prof. olger Stark Dr. Mark Rogers-Evans Dr. Konrad Bleicher Dr. Alexander Alanine Aventis Pharma Deutschland Gmb Beilstein-Institut zur örderung der Chemischen Wissenschaften Daylight Chemical Information Systems Inc.. offmann-la Roche AG onds der Chemischen Industrie (CI)