1. Pistoia Alliance HELM Project An Open Standard for the Representation of Complex Biomolecules Best Practices in Personalized And Translational Medicine Molecular Med Tri-Conference 2015 February 16, 2015 Sergio H. Rotstein, Ph.D.

2. © Pistoia Alliance Background Pfizer Goal –“Top-tier biotherapeutics company” But supporting informatics infrastructure lacking Biomolecules Team Goal –Working on therapeutic oligonucleotides since 2008 –Build on this work to support additional entities for Registration Visualization Analysis and design Workflows –Make biomolecules “first-class citizens” of the informatics tool portfolio HELM is one result of this initiative

3. © Pistoia Alliance What is a “Biomolecule” Peptides Biomolecule: Anything that is not a small molecule

4. © Pistoia Alliance Stuck in the middle… Small Molecules Sequences Biomolecules Small Molecule Tools Sequence-Based Tools

5. © Pistoia Alliance “Fit-for-Purpose” Structure Representation Ab MTTSASSHLNKGIKQVYMSLPQGEKVQAMYIWIDGTGEGLRCKTRTLDSEPKCVEELPEWNFDGSSTLQSEGSNSDM YLVPAAMFRDPFRKDPNKLVLCEVFKYNRRPAETNLRHTCKRIMDMVSNQHPWFGMEQEYTLMGTDGHPFGWPSN GFPGPQGPYYCGVGADRAYGRDIVEAHYRACLYAGVKIAGTNAEVMPAQWEFQIGPCEGISMGDHLWVARFILHRVC EDFGVIATFDPKPIPGNWNGAGCHTNFSTKAMREENGLKYIEEAIEKLSKRHQYHIRAYDPKGGLDNARRLTGFHETSNI NDFSAGVANRSASIRIPRTVGQEKKGYFEDRRPSANCDPFSVTEALIRTCLLNETGDEPFQYKN

6. © Pistoia Alliance Hierarchical Editing Language for Macromolecules Hierarchical –Supports multi-level structures Complex Polymer ⇒ Simple Polymer ⇒ Monomer ⇒ Atom Extensible –Allows addition of new polymer types E.g. Polysaccharides Able to handle entity complexity Oligonucleotide hybridization Chemically modified Biologics –Unnatural amino acids –Bioconjugates

7. © Pistoia Alliance Examples HELM notation RNA1{R(G)P.R(G)P.R(C)P.R(A)P.R(C)P.R(U)P.R(U)P.R(C)P.R(G)P.R(G)P.R(U)P.R(G)P.R(C)P.R(C) }$$RNA1,RNA1,11:pair-32:pair|RNA1,RNA1,5:pair-38:pair|RNA1,RNA1,14:pair- 29:pair|RNA1,RNA1,8:pair-35:pair|RNA1,RNA1,2:pair-41:pair$$ HELM notation PEPTIDE1{A.R.G.[dF].C.K.[meA].E.D.A}$$$$

8. © Pistoia Alliance HELM at Pfizer: Drawing Editor Centralized Monomer DB (smiles, InChI, mol)

9. © Pistoia Alliance HELM at Pfizer: Registration Compound Registration

10. © Pistoia Alliance HELM at Pfizer: Analysis & Design PFRED PFRED: A computational tool for siRNA and antisense design. Simon Xi, Qing Cao, Christine Lawrence, Tianhong Zhang, Simone Sciabola, Sergio Rotstein, Jason Hughes, Daniel Caffrey, and Robert Stanton, PLOS ONE, Submitted

11. © Pistoia Alliance HELM at Pfizer: Workflow 11 AntibodyLinker PayloadADCWorkflow

12. © Pistoia Alliance The Pistoia Alliance 31 st October 2014Presentation title12 The Pistoia Alliance is a global, non- profit alliance of life science companies, vendors, publishers, and academic groups that work together to solve common problems and lower barriers to innovation in R&D

13. © Pistoia Alliance

14. Pistoia HELM Project Goal Transition HELM technology from Pfizer proprietary to Open Source –Provide an industry-wide standard for data exchange within and between organizations –Reduce software development costs by minimizing the need for companies to develop similar functionality

15. © Pistoia Alliance OpenHelm.Org Specification Documentation Tutorials Link to source code Please join our mailing list!

16. © Pistoia Alliance GitHub API HELM Notation Toolkit HELM Editor https://github.com/PistoiaHELM Source Code HELM Drawing Applet

17. © Pistoia Alliance HELM For You: Different strokes… 17 Biomolecule Data Exchange Mechanism Foundation for your biomolecule informatics infrastructure Registration Visualization Analysis and design Workflows Level of Adoption

18. © Pistoia Alliance The HELM Ecosystem Pharma / Biotech / Institutes –BMS, GSK, Lundbeck, Merck, Novartis, Pfizer, Roche Software vendors –ACD/Labs, Arxspan, Biochemfusion, BioMax, Biovia, ChemAxon, NextMove, Scilligence Content / Service Providers –EBI (ChEMBL), eMolecules, quattro Active discussions on-going with others –e.g. FDA

19. © Pistoia Alliance Recent Developments In-Line HELM Notation Exchangeable HELM Roche Antibody Editor Search POC ChEMBL v20 PEPTIDE1{G.[[*]N[C@@H](C=O)C([*])=O |$_R1;;;;;;_R2;$|].C}$$$$ Andreas Bender Group UNIVERSITY OF CAMBRIDGE Peter MacCallum, Andrea Chlebikova

20. © Pistoia Alliance HELM Phase 2 Started in November Areas of focus (prioritized by steering committee) –Continued dissemination and adoption –Technical work to maximize utility and adoptability Management of ambiguity Mitigate dependencies on commercial libraries –Graphing –Chemical toolkit Search 20

21. © Pistoia Alliance Best Practices Share the wealth –Does your organization have “shareable” assets that others could benefit from? Don’t go it alone –“NIH Syndrome” is a luxury none of us can afford Volunteer army, paid sergeant(s) –It has to be someone’s job to keep things moving Time’s fun when you’re having flies -- Kermit the Frog –Everything works much better when the atmosphere is kept light and friendly 31 st October 2014Presentation title21

22. © Pistoia Alliance HELM Team Members Our team Members (Subteam leads) Akos Papp (ChemAxon) Alex Allardyce (ChemAxon) Alex Drijver (ChemAxon) Andrey Yerin (ACD labs) Dana Vanderwall (BMS) Ed Currie (InfoSys) Edvard Buki (ChemAxon) Hans de Bie (ACDLabs) Ian Stott (Unilever) Jerry Winter (Unilever) Jinbo Lee (Scilligence) John Smith (GSK) John Wise (Pistoia) Keith Taylor (Ladera) Kirti Jindal (InfoSys) Matthias Nolte (BMS) Michael Cui (GSK) Mike Travers (CDD) Rama Bhamidpati (GSK) Roland Knispel (ChemAxon) Roland Molnar (ChemAxon) Sergio Rotstein (Pfizer) Stefan Klostermann (Roche) Ted Slater (OpenBEL) Tianhong Zhang (Pfizer) Tony Yuan (Scilligence) Our Steering Committee John Wise (Pistoia Alliance) Margret Assfalg (Roche) Leah O'Brien (GSK) Ramesh Durvasula (BMS) Sergio Rotstein (Pfizer) Alex Drijver (ChemAxon) Chris Waller (Merck) Our Excellent Project Manager Claire Bellamy Special thanks to ChemAxon for their generous contribution of software development resources!! Special thanks to Pfizer for their unwavering support and contribution of in-kind project resources!!

23. © Pistoia Alliance 23 www.OpenHelm.org info@openhelm.org