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
23 Mar
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
35 Mar
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
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