Certara, Inc. · NASDAQ:CERT

Certara — Technical Presentation (June 2013)

56 slides from Certara's technical presentation, June 2013

  1. Slide 1: Multi-criteria Scoring: Combine scoring functions to invent structures

    Multi-criteria Scoring: Combine scoring functions to invent structures which meet multiple design criteria Alexander Steudle, Ph.D. June 2013

  2. Slide 2: Today's Presenter

    Today’s Presenter • Alexander Steudle, Ph.D. – Application Scientist – Scientific consultant in molecular modeling – Works on a variety of CADD projects – Ph.D. in Computational Biology – Prior to Certara, postdoctoral research at the Institute of Technical Biochemistry, University of Stuttgart – Fo

  3. Slide 3: Multi-Criteria Drug Design

    Multi-Criteria Drug Design Criteria Range Mol. Weight 200-400 LogP 0.0-3.0 TPSA 30.0-75.0 HB Donor 0.0-4.0 HB Acceptor 2.0-6.0 Lipinski Viol. 1 Tanimoto 0.3-0.65 Rimonabant © Copyright 2013 Certara, L.P. All rights reserved. 3

  4. Slide 4: Multi-Criteria Drug Design

    Multi-Criteria Drug Design Criteria Range Mol. Weight 200-400 LogP 0.0-3.0 TPSA 30.0-75.0 HB Donor 0.0-4.0 HB Acceptor 2.0-6.0 Lipinski Viol. 1 Tanimoto 0.3-0.65 Desired: High shape and pharmacophore similarity (Surflex-Sim) Rimonabant © Copyright 2013 Certara, L.P. All rights reserved. 4

  5. Slide 5: Multi-Criteria Drug Design

    Multi-Criteria Drug Design Criteria Range 1 2 3 4 5 6 7 Mol. Weight 200-400 382.54 305.8 382.54 370.87 382.54 373.91 370.87 LogP 0.0-3.0 1.8 2.2 1.7 2.6 1.7 2.6 2.6 TPSA 30.0-75.0 73.18 44.7 73.18 62.88 73.18 47.86 62.88 HB Donor 0.0-4.0 4 1 4 2 4 2 2 HB Acceptor 2.0-6.0 5 4 5 5 5 4 5 Tanimoto 0.3-0

  6. Slide 6: The Problem

    The Problem • Compounds exist that have some desirable properties to become a drug but… • The known compounds are not suitable due to: – Intellectual Property – Physical Properties – DMPK Properties – Toxicological Properties – Each with it’s own SAR!! © Copyright 2013 Certara, L.P. All rights reser

  7. Slide 7: Muse Invention: Software for multi-criteria molecular design

    Muse Invention: Software for multi-criteria molecular design Seed Structures Population of Parents (With Scores) © Copyright 2013 Certara, L.P. All rights reserved. 7

  8. Slide 8: Muse Invention: Software for multi-criteria molecular design

    Muse Invention: Software for multi-criteria molecular design • 34 structure-modifying operators • May preserve substructure(s) • May tailor evolutionary process • May add custom fragment library • May exclude undesirable chemistry Seed Structures Invent Population Population of Parents Of Children (

  9. Slide 9: Muse Invention: Software for multi-criteria molecular design

    Muse Invention: Software for multi-criteria molecular design • 34 structure-modifying operators • May preserve substructure(s) • May tailor evolutionary process • May add custom fragment library • May exclude undesirable chemistry Seed Structures Invent Population Population of Parents Of Children (

  10. Slide 10: Muse Invention: Software for multi-criteria molecular design

    Muse Invention: Software for multi-criteria molecular design • 34 structure-modifying operators • May preserve substructure(s) • May tailor evolutionary process • May add custom fragment library • May exclude undesirable chemistry Seed Structures Invent Population Population of Parents Of Children (

  11. Slide 11: Muse Invention: Software for multi-criteria molecular design

    Muse Invention: Software for multi-criteria molecular design • 34 structure-modifying operators • May preserve substructure(s) • May tailor evolutionary process • May add custom fragment library • May exclude undesirable chemistry Seed Structures Invent Population Population of Parents Of Children (

  12. Slide 12: Analyzing invented structures: Spreadsheet

    Analyzing invented structures: Spreadsheet Color by value, multi sort, filter, calc. properties Substructure / Similarity search Import/Export: SLN, MOL2, SDF, SMILES © Copyright 2013 Certara, L.P. All rights reserved.

  13. Slide 13: Analyzing invented structures: Charts

    Analyzing invented structures: Charts © Copyright 2013 Certara, L.P. All rights reserved. 13

  14. Slide 14: Agenda

    Agenda • Built in Multi-Criteria Scoring Functions – Multi-Criteria Scoring using Muse TriposScore – Include ADME/Tox properties in Muse TriposScore – Multi-Criteria Scoring using Docking • Combined Multi-Criteria Scoring Function – A Customer example • Custom Multi-Criteria Scoring Function using K

  15. Slide 15: Multi-Criteria Scoring using Muse TriposScore

    Multi-Criteria Scoring using Muse TriposScore © Copyright 2013 Certara, L.P. All rights reserved.

  16. Slide 16: Muse TriposScore – Multi-Criteria Ligand Based Scoring

    Muse TriposScore – Multi-Criteria Ligand Based Scoring Tanimoto similarity: 0.39 © Copyright 2013 Certara, L.P. All rights reserved. 16

  17. Slide 17: Muse TriposScore Retrospective Example

    Muse TriposScore Retrospective Example • NK1 receptor antagonist CP99994 Starting point Muse inventions Known actives O O N N O N N N Pfizer: WO2005115976 N O O N N CP99994 N N Pfizer: WO9206079 NovoFLAP: A Ligand-Based De Novo Design Approach for the Generation of Medicinally Relevant Ideas. J.R. D

  18. Slide 18: Multi-Criteria Composable Scoring Via KNIME

    Multi-Criteria Composable Scoring Via KNIME © Copyright 2013 Certara, L.P. All rights reserved. 18

  19. Slide 19: Multi-Criteria Composable Scoring Via KNIME

    Multi-Criteria Composable Scoring Via KNIME © Copyright 2013 Certara, L.P. All rights reserved. 19

  20. Slide 20: Multi-Criteria Composable Scoring Via KNIME

    Multi-Criteria Composable Scoring Via KNIME Read invented compounds, calculate properties, Lipinski filter © Copyright 2013 Certara, L.P. All rights reserved. 20

  21. Slide 21: Multi-Criteria Composable Scoring Via KNIME

    Multi-Criteria Composable Scoring Via KNIME Read invented compounds, calculate properties, Lipinski filter Read “bad” structures, calculate & compare UNITY fingerprints, filter compounds if too close © Copyright 2013 Certara, L.P. All rights reserved. 21

  22. Slide 22: Multi-Criteria Composable Scoring Via KNIME

    Multi-Criteria Composable Scoring Via KNIME Read invented compounds, calculate properties, Lipinski filter Read “bad” structures, calculate & compare UNITY fingerprints, filter compounds if too close Read reference structures, calculate & compare UNITY fingerprints © Copyright 2013 Certara, L.P. All

  23. Slide 23: Multi-Criteria Composable Scoring Via KNIME

    Multi-Criteria Composable Scoring Via KNIME Read invented compounds, calculate properties, Lipinski filter Read “bad” structures, calculate & compare UNITY fingerprints, filter compounds if too close Read reference structures, calculate & compare UNITY fingerprints Flexible 3D shape & pharmacophore

  24. Slide 24: Change Muse TriposScore to include ADME/Tox properties

    Change Muse TriposScore to include ADME/Tox properties © Copyright 2013 Certara, L.P. All rights reserved.

  25. Slide 25: ADME Scoring Function

    ADME Scoring Function The p38 ligands are mainly predicted to be permeable by the VolSurf+ Caco2 model © Copyright 2013 Certara, L.P. All rights reserved. 25

  26. Slide 26: ADME Scoring Function

    ADME Scoring Function Muse invents structures ranging from poor to high permeability © Copyright 2013 Certara, L.P. All rights reserved. 26

  27. Slide 27: ADME scoring function

    ADME scoring function Adding the VolSurf+ Caco2 model to the Muse scoring function - the population is more tightly focused in the permeable region © Copyright 2013 Certara, L.P. All rights reserved. 27

  28. Slide 28: ADME Scoring Function

    ADME Scoring Function © Copyright 2013 Certara, L.P. All rights reserved. 28

  29. Slide 29: © Copyright 2013 Certara, L.P. All rights reserved.

    © Copyright 2013 Certara, L.P. All rights reserved. 29

  30. Slide 30: Multi-Criteria Scoring using Docking

    Multi-Criteria Scoring using Docking © Copyright 2013 Certara, L.P. All rights reserved.

  31. Slide 31: Surflex-Dock: PPAR-γ fragment growing

    Surflex-Dock: PPAR-γ fragment growing 1FM6, Rosiglitazone © Copyright 2013 Certara, L.P. All rights reserved. 31

  32. Slide 32: Surflex-Dock: PPAR-γ fragment growing

    Surflex-Dock: PPAR-γ fragment growing MW between 250 and 400 LogP between -1 and 5 HBD, HBA: between 1 and 5 Placed fragment = preserved core © Copyright 2013 Certara, L.P. All rights reserved. 32

  33. Slide 33: Surflex-Dock: PPAR-γ fragment growing

    Surflex-Dock: PPAR-γ fragment growing High ranking invention results © Copyright 2013 Certara, L.P. All rights reserved. 33

  34. Slide 34: p38 MAP kinase inhibitors from Derwent WDA

    p38 MAP kinase inhibitors from Derwent WDA • Goal: Examine MUSE engine’s performance in scaffold hopping • Reproducing known ligand cores • Suggesting new cores • 209 entries exported • 96 structurally unique ones under binding mode #2 • Fixed fragment “2-fluoro-4-chlorophenyl” mapped onto ligand in

  35. Slide 35: Examples of core structures in known inhibitors

    Examples of core structures in known inhibitors Cl Cl Cl A F B F Cl Cl Cl Cl H Cl F N F B A C D HN F F F F HN H N N O N S N a b X a b a b X a N N N N O N O HN O H H O a, b: 5/6R/FR; a, b: 5/6R a, b: 5/6R; a: 6R (WD-2002-014979) (WD-2003-011736) (WD-1999-011420) (WD-2002-014979) X: N/O/=O X: N/O/=O C

  36. Slide 36: MUSE structures invented in 7/8 core types

    MUSE structures invented in 7/8 core types Cl Cl Cl Cl Cl Cl Cl A B Cl F B D A C F F F F F F F H HN N S NH a b X a b a b X a N O O N HN N O N O N H N N H a, b: 5/6R/FR; a, b: 5/6R a, b: 5/6R; a: 6R X: N/O/=O X: N/O/=O 9 10 11 12 Cl Cl Cl Cl Cl Cl Cl Cl C E F G H F F F O F F F F F H X S S N O a X a b

  37. Slide 37: MUSE structures in the 10 new core types

    MUSE structures in the 10 new core types Cl Cl Cl Cl Cl Cl Cl Cl A1 B1 A1 B1 F C1 C2 F F F F F F b a F a b X a b a O O H N N b N N a, b: 5/6R; a: 6R; b: 5R O X: N/=O a, b: 5/6R H a: 6R; b: 5/6R/FR O N N N N H O Cl Cl Cl N N O O Cl N N O D1 D2 E1 E2 H N 25 26 27 28 F F F F (C,S) O O a O a a Cl Cl Cl

  38. Slide 38: A Customer Created Multi-Criteria Combined Scoring Function

    A Customer Created Multi-Criteria Combined Scoring Function © Copyright 2013 Certara, L.P. All rights reserved.

  39. Slide 39: Muse Scoring: Bioisoster design

    Muse Scoring: Bioisoster design © Copyright 2013 Certara, L.P. All rights reserved. 39

  40. Slide 40: Invention Workflow

    Invention Workflow Generate initial population from seed structure or from scratch Filter Unwanted chemistry Convergence reached Bioisosters Filter PAINS (Pan Assay Interference Compounds) Muse Selection, genetic Scoring 1 Scoring 2 Scoring 3 operators Structural diversity Shape and pharmacophore Sy

  41. Slide 41: Scoring Functions created and used by our customers

    Scoring Functions created and used by our customers • Molegro • Volsurf+ • GOLD • GLIDE • Shaep/Balloon • Quantum Mechanics Muse Invention plays its true • Topomer Search strength by combining different scoring functions! • 3D QSAR/CoMFA • UNITY Pharmacophore • Synthetic Feasibility • 2D QSAR • E-Dr

  42. Slide 42: Implementation methods used by our customers

    Implementation methods used by our customers • Perl • Python • Bash Scripting • Pipeline Pilot • KNIME © Copyright 2013 Certara, L.P. All rights reserved. 42

  43. Slide 43: Multi-Criteria Scoring using KNIME revisited

    Multi-Criteria Scoring using KNIME revisited © Copyright 2013 Certara, L.P. All rights reserved.

  44. Slide 44: Scoring Compounds using Shape, Volume & Scaffold

    Scoring Compounds using Shape, Volume & Scaffold • Open source nodes installed (CDK, RDKit) • Read SDF files, calculate similarity to reference using – Ultra fast shape similarity (USR1) – VABCVolume3 (fast calculation of van der Waals Volume) – Charge weighted topological structure autocorrelation2

  45. Slide 45: Scoring Compounds using Shape, Volume & Scaffold

    Scoring Compounds using Shape, Volume & Scaffold © Copyright 2013 Certara, L.P. All rights reserved. 45

  46. Slide 46: Scoring Compounds using Shape, Volume & Scaffold

    Scoring Compounds using Shape, Volume & Scaffold © Copyright 2013 Certara, L.P. All rights reserved. 46

  47. Slide 47: Scoring Compounds using Shape, Volume & Scaffold

    Scoring Compounds using Shape, Volume & Scaffold © Copyright 2013 Certara, L.P. All rights reserved. 47

  48. Slide 48: Scoring Compounds using Shape, Volume & Scaffold

    Scoring Compounds using Shape, Volume & Scaffold © Copyright 2013 Certara, L.P. All rights reserved. 48

  49. Slide 49: Scoring Compounds using Shape, Volume & Scaffold

    Scoring Compounds using Shape, Volume & Scaffold © Copyright 2013 Certara, L.P. All rights reserved. 49

  50. Slide 50: Scoring Compounds using Shape, Volume & Scaffold

    Scoring Compounds using Shape, Volume & Scaffold © Copyright 2013 Certara, L.P. All rights reserved. 50

  51. Slide 51: Scoring Compounds using Shape, Volume & Scaffold

    Scoring Compounds using Shape, Volume & Scaffold © Copyright 2013 Certara, L.P. All rights reserved. 51

  52. Slide 52: Scoring Compounds using Shape, Volume & Scaffold

    Scoring Compounds using Shape, Volume & Scaffold Starting point Muse inventions Known actives O O N N O N N N Pfizer: WO2005115976 N O O N N CP99994 N N Pfizer: WO9206079 © Copyright 2013 Certara, L.P. All rights reserved. 52

  53. Slide 53: Muse Invention Science

    Muse Invention Science Publications: • Automated generation of turn mimetics: Proof of concept study for the MC4 receptor. J.C. Baber, R. Lowe, J. Saunders, M. Feher, Bioorg. & Med. Chemistry, 2012, 20(11), 3565-74 • Atom Coloring for Chemical Interpretation and De Novo Design for Molecular Design.

  54. Slide 54: Summary

    Summary • Internal available Multi-Criteria Scoring Functions – Muse TriposScore – Change of Muse TriposScore to include ADME/Tox properties – Surflex-Dock • Customer Based Multi-Criteria Scoring Function – Bioisoster • Open Source Multi-Criteria Scoring Function – KNIME © Copyright 2013 Certara, L.

  55. Slide 55: Muse – How can I Learn More?

    Muse – How can I Learn More? • Other Webinars - on www.certara.com • Scientific Publications • Product Sheet - on www.certara.com • Request an Evaluation © Copyright 2013 Certara, L.P. All rights reserved.

  56. Slide 56: Contacts & Follow-Up: Thank you!

    Contacts & Follow-Up: Thank you! For more information regarding today’s presentation, please contact: Alexander Steudle, PhD., Application Scientist alexander.steudle@certara.com For more information on Certara’s products & services, please contact our sales group: Americas India Email: sales@certar

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