Alex Clark : NETTAB 2013
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Cheminformatics workflows using the mobile + cloud platform. Presentation by Dr. Alex M. Clark of Molecular Materials Informatics at the NETTAB 2013 meeting in Venice, Italy. The presentation introduces the significance of mobile apps in science, and the scope of their capabilities in chemical structure informatics. The bulk of the talk describes an account of a preliminary workflow using open science data to search for viable leads for a cure for tuberculosis. The workflow described makes use of a combination of mobile, cloud and conventional desktop-based technology, all stitched together by facile communication, sharing and collaboration features.
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Alex Clark : NETTAB 2013
- 1. Cheminformatics workflows using the mobile + cloud platform Dr. Alex M. Clark October 2013 © 2013 Molecular Materials Informatics, Inc. http://molmatinf.com
- 2. MOLECULAR MATERIALS INFORMATICS Overview • Chemical structures • Mobile apps • Cloud computing 2
- 3. MOLECULAR MATERIALS INFORMATICS 3 3rd Revolution mainframes minicomputers personal computers portable laptops mobile tablets smartphones • The mobile platform is revolutionary: a clean break - entirely new user interface no backward compatibility highly constrained resources applicable to entirely new situations
- 4. MOLECULAR MATERIALS INFORMATICS 4 Two platform stacks desktop/ laptop phone/ tablet file/database server web services compute cluster cloud resources
- 5. MOLECULAR MATERIALS INFORMATICS 5 Delivery Apps • User experience Cloud • Web API • Cached data • Heavy calculations • Light calculations • Large data • Sharing • Centralised storage
- 6. MOLECULAR MATERIALS INFORMATICS Challenges • Mobile user interfaces are completely different to desktop products • Expectations: functionality, extreme simplicity • Complex interfaces much harder: drawing chemical structures requires redesign • Visualisation is more difficult: screen size • Storage limitations: big data is a problem • Calculations split mobile vs. cloud 6
- 7. MOLECULAR MATERIALS INFORMATICS 7 App Catalog Mobile Molecular DataSheet (MMDS) Green Solvents Living Molecules MolSync SAR Table MolPrime+ MolPrime Lab Solvents Approved Drugs Reaction101 Yield101 SPRESImobile Open Drug Discovery Teams TB Mobile ChemSpider
- 8. MOLECULAR MATERIALS INFORMATICS Drawing Structures • Cheminformatics requires a user interface for drawing structures • Interface needs to be: - capable for complex structures publication quality fast to use phone-size form factor • Traditional interface paradigm on touchscreen: unusable... 8
- 9. MOLECULAR MATERIALS INFORMATICS Drawing Reactions • Components: reuse sketcher, iPhone friendly • Higher level of markup useful for lab notebooks • Used by MMDS, Reaction101, Yield101 9
- 10. MOLECULAR MATERIALS INFORMATICS Assembling DataSheets • MMDS: molecular datasheet unit - molecular structures - reaction schemes - scalar data (text, numbers) • Table-like structure, roughly equivalent to SDfile/RDfile • Operate on individual rows or whole datasheets 10
- 11. MOLECULAR MATERIALS INFORMATICS Scaffolds & Substituents • Scaffold-centric model useful to drug discovery • SAR Table app: optimised for data entry • And: analysis, visualisation and calculation 11
- 12. MOLECULAR MATERIALS INFORMATICS Searching • App interfaces for structure searching 12
- 13. MOLECULAR MATERIALS INFORMATICS Calculation • Structures used to calculate properties • Single molecules, or whole datasheets • Simple calculations: done by app • Difficult calculations: use webservice 13
- 14. MOLECULAR MATERIALS INFORMATICS Importing • Receive recognised filetypes - clipboard email web other apps (IPC) webservices remote filesystems • Documented formats, e.g. SketchEl, MDL, ChemDraw, CML 14
- 15. MOLECULAR MATERIALS INFORMATICS Exporting • Apps are only as good as their ability to use the data • Export actual data using cheminformatics formats - clipboard email web sharing twitter webservices remote filesystems 15
- 16. MOLECULAR MATERIALS INFORMATICS Graphics • Prepare bitmapped graphics for: - clipboard - photo roll - email • Can incorporate into other apps on the device (e.g. Keynote) • Vector graphics: SVG, EPS, Microsoft Word & Excel 16
- 17. MOLECULAR MATERIALS INFORMATICS Sharing • Share data publicly or privately • Upload to a webservice - store raw data - dynamically render - hosted by molsync.com • Tweet directly from the app: share the link 17
- 18. Real world workflow: searching for new Tuberculosis drugs Dr. Alex M. Clark October 2013 © 2013 Molecular Materials Informatics, Inc. http://molmatinf.com
- 19. MOLECULAR MATERIALS INFORMATICS Outline • Workflow is representative of lead discovery • Searching for new Mycobacterium tuberculosis drugs • Open data, open science, collaborating with experimentalists • Workflow involves: http://molmatinf.com/ venice.html - mobile apps - cloud-based webservices - traditional software 19
- 20. MOLECULAR MATERIALS INFORMATICS TB Mobile • Curated data for tuberculosis drugs • iOS & Android • CDD, NIAID grant, Sean Ekins • App presents a browseable list of structures • Can filter by target, sort by structural similarity • Visual data exportable.... 20
- 21. MOLECULAR MATERIALS INFORMATICS A Good Scaffold • Objective: use the data from TB Mobile to find a scaffold, then use to infer gene target from a larger collection of SAR data • What makes a good scaffold? 21
- 22. MOLECULAR MATERIALS INFORMATICS Methodology • Preliminary work done with desktop software: com.mmi • Fragment TB Mobile structures, scaffold-like • Perform scaffold-substructure vs. 7000 in vitro • Derive R-groups, tidy, present graphically, browse... http://molmatinf.com/venice.html 22
- 23. MOLECULAR MATERIALS INFORMATICS Source Materials • Scaffold: • Scaffold origin: inhibitor of Glf target • 87 molecules with in vitro activity (yes/no) • Scaffold seems to elicit an activity pattern • Next step: load it into the app ecosystem... 23
- 24. MOLECULAR MATERIALS INFORMATICS Importing • Email attachment to self: open in SAR Table 24
- 25. MOLECULAR MATERIALS INFORMATICS Raw DataSheet • Just Molecule and Activity... 25
- 26. MOLECULAR MATERIALS INFORMATICS Draw Scaffold • Select first row • Use built in sketcher to draw scaffold 26
- 27. MOLECULAR MATERIALS INFORMATICS Draw Scaffold • Select first row • Use built in sketcher to draw scaffold 26
- 28. MOLECULAR MATERIALS INFORMATICS Substituent Fields • R-group labels: offer to create fields 27
- 29. MOLECULAR MATERIALS INFORMATICS Scaffold & Molecule • Need to assign substituents: automatically 28
- 30. MOLECULAR MATERIALS INFORMATICS Scaffold Matching • Perform single scaffold:molecule match 29
- 31. MOLECULAR MATERIALS INFORMATICS Scaffold Matching • Perform single scaffold:molecule match 29
- 32. MOLECULAR MATERIALS INFORMATICS Scaffold Matching • Perform single scaffold:molecule match 29
- 33. MOLECULAR MATERIALS INFORMATICS Bulk Matching • Duplicate scaffold, match to all molecules 30
- 34. MOLECULAR MATERIALS INFORMATICS Bulk Results • Only unambiguous results are provided 31
- 35. MOLECULAR MATERIALS INFORMATICS Bulk Results • Only unambiguous results are provided 31
- 36. MOLECULAR MATERIALS INFORMATICS Symmetry/Degeneracy • Two possible results: note degeneracy R4,R6 32
- 37. MOLECULAR MATERIALS INFORMATICS Symmetry/Degeneracy • Two possible results: note degeneracy R4,R6 32
- 38. MOLECULAR MATERIALS INFORMATICS Finishing Assignment • Single & bulk scaffold matching: semiautomated assignment, human tiebreakers • Have 87 compounds, 21 active against TB • Based on scaffold from a binder of Glf enzyme (essential for mycobacterial growth) • What next? • Look for other compounds: same scaffold 33
- 39. MOLECULAR MATERIALS INFORMATICS Searching • Search public databases using template 34
- 40. MOLECULAR MATERIALS INFORMATICS Searching • Search public databases using template 34
- 41. MOLECULAR MATERIALS INFORMATICS Search Results • Results come back with scaffolds assigned 35
- 42. MOLECULAR MATERIALS INFORMATICS Sources • Data from ChemSpider, PubChem, ChEBI • Includes database links and vendor information 36
- 43. MOLECULAR MATERIALS INFORMATICS Importing • Search results imported in marked-up form 37
- 44. MOLECULAR MATERIALS INFORMATICS Model Building • Use known activities to build a SAR model 38
- 45. MOLECULAR MATERIALS INFORMATICS Model Application • Predicted activities shown as coloured wedges 39
- 46. MOLECULAR MATERIALS INFORMATICS Selected Candidates • Compile a list: predicted activity > 0.8 • Open in Mobile Molecular DataSheet (MMDS) app 40
- 47. MOLECULAR MATERIALS INFORMATICS Selected Candidates • Compile a list: predicted activity > 0.8 • Open in Mobile Molecular DataSheet (MMDS) app 40
- 48. MOLECULAR MATERIALS INFORMATICS Sharing by Email • Very easy to share using email attachments • Recipient can open on any device, including mobile 41
- 49. MOLECULAR MATERIALS INFORMATICS Sharing by Email • Very easy to share using email attachments • Recipient can open on any device, including mobile 41
- 50. MOLECULAR MATERIALS INFORMATICS Sharing by Email • Very easy to share using email attachments • Recipient can open on any device, including mobile 41
- 51. MOLECULAR MATERIALS INFORMATICS Sharing via Dropbox • MMDS can interact with MolSync app • DataSheets are uploaded & synchronised in Dropbox 42
- 52. MOLECULAR MATERIALS INFORMATICS MolSync & Dropbox • MolSync app is a chemistry-aware file browser • Can make use of Dropbox's collaboration features 43
- 53. MOLECULAR MATERIALS INFORMATICS Lookup FDA Reference • Open With the Approved Drugs app 44
- 54. MOLECULAR MATERIALS INFORMATICS Approved Drugs • 1300 structures for FDA-approved drugs • Reference search by structural similarity 45
- 55. MOLECULAR MATERIALS INFORMATICS Matrix View • Plot structures in a grid: R1 vs R5 46
- 56. MOLECULAR MATERIALS INFORMATICS Matrix View • Plot structures in a grid: R1 vs R5 46
- 57. MOLECULAR MATERIALS INFORMATICS Matrix + Predictions • Compounds with unknown activity predicted shown using wedge style 47
- 58. MOLECULAR MATERIALS INFORMATICS Matrix + Hypotheticals • Empty squares: propose compounds & predict 48
- 59. MOLECULAR MATERIALS INFORMATICS Matrix + Hypotheticals • Empty squares: propose compounds & predict 48
- 60. MOLECULAR MATERIALS INFORMATICS Proposing Compounds • Tap on a square: prompt to create partially defined entry, defining R1 and R5 49
- 61. MOLECULAR MATERIALS INFORMATICS Hypothetical Compound • New compound added: partial definition • R2, R3, R4 and R6 unspecified 50
- 62. MOLECULAR MATERIALS INFORMATICS Lookup in SPRESI • Use SPRESImobile app to find similar compounds: looking for a synthesis... 51
- 63. MOLECULAR MATERIALS INFORMATICS Similar Backbone • Found a compound with similar core, possible synthesis template: consult literature 52
- 64. MOLECULAR MATERIALS INFORMATICS Find Reactions • Lookup synthetic routes: amide condensation • Open the reaction data in Yield101 53
- 65. MOLECULAR MATERIALS INFORMATICS Find Reactions • Lookup synthetic routes: amide condensation • Open the reaction data in Yield101 53
- 66. MOLECULAR MATERIALS INFORMATICS Find Reactions • Lookup synthetic routes: amide condensation • Open the reaction data in Yield101 53
- 67. MOLECULAR MATERIALS INFORMATICS Yield101 • Prototype synthetic chemistry lab notebook • Reaction components imported 54
- 68. MOLECULAR MATERIALS INFORMATICS Reaction Scheme • Tidyup structures, add in reagent 55
- 69. MOLECULAR MATERIALS INFORMATICS Lookup Starting Material • Use Mobile Reagents integration to find commercial source for starting material 56
- 70. MOLECULAR MATERIALS INFORMATICS Lookup in ChemSpider • Paste into ChemSpider Mobile app to do structure search • Open matching ChemSpider compound information page 57
- 71. MOLECULAR MATERIALS INFORMATICS Lookup in ChemSpider • Paste into ChemSpider Mobile app to do structure search • Open matching ChemSpider compound information page 57
- 72. MOLECULAR MATERIALS INFORMATICS Quantitative Details • Enter starting quantity, density: preliminary estimate of amounts used in synthesis 58
- 73. MOLECULAR MATERIALS INFORMATICS Public Sharing • Upload scheme to molsync.com • Generates publicly sharable link 59
- 74. MOLECULAR MATERIALS INFORMATICS Shared Content • Stores chemical data in its native form: - molecules - reaction schemes - datasheets • Can share, tweet, etc. • Download data in many different forms... 60
- 75. MOLECULAR MATERIALS INFORMATICS Shared Content • Stores chemical data in its native form: - molecules - reaction schemes - datasheets • Can share, tweet, etc. • Download data in many different forms... 60
- 76. MOLECULAR MATERIALS INFORMATICS Numerous Formats • Sharing site stores pure data, creates preview graphics dynamically... and interconversions Molecules • SketchEl • MDL MOL • CML Reactions • DataSheet XML • MDL RXN • MDL RDF Collections • DataSheet XML • MDL SDfile Raster Graphics • PNG • PNG ZIP Vector Graphics • SVG • SVG ZIP • HTML SVG • EPS • MS Word • MS Excel 61
- 77. MOLECULAR MATERIALS INFORMATICS 62 Vector Graphics • Quality is perfect at all resolutions: screen, projector, web, printer, PDF... Vector Bitmap
- 78. MOLECULAR MATERIALS INFORMATICS Microsoft Office Documents • Independent implementation of OOXML spec • Embedded graphics use vector DrawingML 63
- 79. MOLECULAR MATERIALS INFORMATICS SAR Table Documents • Scaffold/substituent tables for manuscripts 64
- 80. MOLECULAR MATERIALS INFORMATICS Matrix PDF • Multi-page layout: print directly or email PDF 65
- 81. MOLECULAR MATERIALS INFORMATICS Tweeting • Can tweet directly from apps like MMDS • First upload data to molsync.com • Then emit tweet with link • Observe list of predefined hashtags: #tuberculosis 66
- 82. MOLECULAR MATERIALS INFORMATICS Open Drug Discovery Teams • Curation of open data, e.g. Twitter & RSS feeds • Rare & neglected diseases, precompetitive areas 67
- 83. MOLECULAR MATERIALS INFORMATICS Harvested Tweet • Tweet got harvested into Tuberculosis topic • Inline preview browsed, with other thumbnails 68
- 84. MOLECULAR MATERIALS INFORMATICS Chemistry Aware • The app understands chemical data • Users can use the data, open with in apps... 69
- 85. MOLECULAR MATERIALS INFORMATICS Rinse & Repeat • Defer to experimentalists: measure activity for selected compounds with predictions • Return to SAR Table app: - provide activity results visualise matrix plot with actual data added rebuild model, regenerate predictions iteratively refine hypothesis • Done using $50 worth of software and tablet • Workflow is appropriate for use by experimentalists 70
- 86. MOLECULAR MATERIALS INFORMATICS Living Molecules • Going beyond desktop-era functionality • Devices have: - long battery life bluetooth location awareness camera! • Observe the strange symbol: molecular glyph 71
- 87. MOLECULAR MATERIALS INFORMATICS Molecular Glyphs • Recognition sequence: point camera • View content, import, manage, utilise, export 72
- 88. MOLECULAR MATERIALS INFORMATICS Conclusion • Cheminformatics workflows historically the role of specialists: expensive and/or complex • Mobile apps are much cheaper and much more accessible to experimentalists • Mobile+cloud can: - replace simple-to-medium tasks - coexist with complex tasks run on desktop software • Other advantages: - anywhere/anytime portability - excellent collaboration and sharing - non-existent installation or maintenance burden 73
- 89. Acknowledgments • Antony Williams http://molmatinf.com/venice.html • Sean Ekins • Joel Freundlich • NETTAB / Bioinformatics Italian Society • InfoChem, Eidogen-Sertanty • Inquiries to info@molmatinf.com http://molmatinf.com http://molsync.com http://cheminf20.org @aclarkxyz