Fragment based drug discovery in teams of medicinal and computational chemists. Carsten Detering

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1 Fragment based drug discovery in teams of medicinal and computational chemists Carsten Detering

2 BioSolveIT Quick Facts Founded in 2001 by the developers of FlexX ~20 people Core expertise: docking, screening, FBLD, GUIs Offers collaborative custom development licenses and contract maintenance training and consulting services Strong scientific backbone: Thomas Lengauer Matthias Rarey Gerhard Klebe Hugo Kubinyi Chris Lipinski Mar

3 The LeadIT/ReCore idea! Mar

4 CompChem MedChem Team Early Stage Teamformation 2011 BioSolve IT GmbH Spring ACS Meeting, Anaheim, CA Mar

5 Link, Merge, Grow Fragments ReCore in LeadIT Mar

6 Case Study: Merging Fragments Mar

7 Fragment Merging The idea: Connect multiple known fragment binders where they overlap. P. Hajduk: Fragment-Based Drug Design at Abbott (Talk at the FBLD'2008, San Diego) and many, many others nowadays. Mar

8 A Tough Merging Example Thymidylate Synthase Inhibition à la Sunesis (Erlanson et al., PAS ) -O 2 C mthf K m : 14mM -O 2 C H O tosyl group is in roughly the same position and orientation as the benzamide moiety of methylenetetrahydrofolate O H COO- H 2 H O O S CO 2 - O O S CO 2 - -O 2 C O H PDB: 1F4E K i : 1.1mM 24mM, further opt d to 330nM Mar

9 A Tough Merging Example Thymidylate Synthase Inhibition à la Sunesis (Erlanson et al., PAS ) -O 2 C -O 2 C H O Published Result ReCore Rank 8 after 1sec. COO- COO- O H O O H 2 S H CO 2 - -O 2 C O H O O S CO 2 - -O 2 C H O O S CO 2 - To ensure the result accommodates in the pocket the input ligand envelope shapes were used. Mar

10 A Tough Merging Example Mar

11 Case Study : Merging Fragments Mar

12 A Fragment Merging Exercise Adenosine Deaminase: Erlanson, D.A. et al.,. J. Med. Chem. 2004, 47, 3463 ff. Mar

13 A Fragment Merging Exercise Adenosine Deaminase: Erlanson, D.A. et al.,. J. Med. Chem. 2004, 47, 3463 ff. 1ndv 2e1w Mar

14 A Fragment Merging Exercise Mar

15 Case study: Growing a Fragment Mar

16 Growing into a p-p Interaction Pattern Bcl-2 protein example from Abbott (Oltersdorf et al, ature 435 (2005) 677). Let us try to get the p-stacking right as in the original finding in ABT-737 O 2 Cl O H SO 2 p H S Site 1 Site 2 2 vectors are needed for the Query: a) Exit Vector b) p-interaction Pharm. Feature O 2 O H SO 2 p Cl Mar

17 Here it is in 3D: Growing into a p-p Interaction Pattern Mar

18 The Result in 2D: Growing into a p-p Interaction Pattern ABT-737 Cl O H SO 2 O 2 H S ReCore Solution o.11: O 2 Cl O H SO 2 H S O O Mar

19 Growing into a p-p Interaction Pattern Solution o. 11 in comparison to ABT-737 (green): Almost identical positions obtained! Mar

20 Software for Medicinal Chemists Mar

21 User Interaction 1 Handle Chemistry 2 Grow With Requirements 3 Make MedChems happy! Mar

22 Roche 2007: Scaffold Hopping Using Vectors define Exit Vectors search 3D fragment library => ReCore. Software development by Maass, Rarey (ZBH, Hamburg) and Roche Maaß, Schulz-Gasch, Stahl Rarey, J. Chem. Inf. Mod., 47, (2007) Mar

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24 Index Generation Index 2011 BioSolve IT GmbH Spring ACS Meeting, Anaheim, CA Mar

25 Standard Workflow Input mol2 Rules O O S H 2 H Reasonable H Fragments Index Index + Mar

26 ReCore: Indexed Searching Mar

27 ReCore: Indexed Searching The Index needs a pre-generated descriptor : Telephone book: alphabet ReCore: Vector relationships Mar

28 Google-like Searching I feel lucky LeeeeeeaaaaaaaaadIT The better the geometric fit, the better the rank Mar

29 ReCore: Results Delivery By design the best fitting replacements are found first The ranking is according to deviation from perfect vector overlap Rank 1 Rank 2 Rank 3 ReCore Query Rank 4 Mar

30 A ReCore Specialty: 3D Shredding q 1 q 2 trivial fragmentation q 1 q 2 partial enumeration Mar

31 Bring in chemists in every step Results Forbid unwanted bond formation Query defintion: Cut where chemists can synthesize Fragment creation: Retrosynthetic shredding rules = sensible fragments Mar

32 Bring in low energy conformations 1. Torsions within the fragment (typically from experiment) ۷ ۷ O ۷ observed prior to indexing S A B 'C Torsions fixed Torsions fixed Torsions fixed 2. Torsions upon new single bonds formation: Link Constraints O O torsions controllable by user, connections can even be forbidden A 'C B Mar

33 Intuitive Interface Mar

34 Wrap-up LeadIT/ReCore in teams Technology Key applications Core replacement Fragment linking & merging Fragment growing Docking (pose checking) Binding affinity assessment Key advantages Low energy conformations (-> bioactivity) 1 Pharmacophores (-> target specificity) 2 Grows with requirements (-> IP) 3 Interactive search (-> TEAM building) Use fragments (-> chemical universe) Index created by user Mar

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36 Wrap-up LeadIT/ReCore in teams Technology Key applications Core replacement Fragment linking & merging Fragment growing Docking (pose checking) Binding affinity assessment Key advantages Low energy conformations (-> bioactivity) 1 Pharmacophores (-> target specificity) 2 Grows with requirements (-> IP) 3 Interactive search (-> TEAM building) Use fragments (-> chemical universe) Index created by user Mar