1. Applying Royal Society of Chemistry Cheminformatics Skills to Support the PharmaSea Project
Antony Williams, Alexey Pshenichnov, Valery Tkachenko, Ken Karapetyan, David Sharpe
ACS San Francisco
August 2014

2. Cancer Deaths Worldwide

3. Top Treatments for Cancer

4. Importance of Natural Products
Over half of all drugs introduced between 1940 and 2006 were of natural origin or inspired by natural compounds

5. Natural Products for all of us!

6. We Are Doomed I Tell You!!!

7. We Are Doomed I Tell You!!!

8. The Dangers of Algal Blooms!

9. Nature’s Little Pharmacy

10. We Are Doomed I Tell You!!!

11. Antibiotic resistance

12. Discovery Curve Decay

13. RSC and Natural Products

15. Focus on Marine Natural Products
RSC cheminformatics support to include:
Deliver “PharmaSea website”
Provide access to natural products subset
Develop “dereplication techniques”
Searching NMR features against database
Develop advanced searches for MS data
Host Open Data from the PharmaSea project and make available to the community

17. The PharmaSea Website
RSC is open-sourcing a chemical registry system as a result of Open PHACTS
Chemical Registry system used to underpin the PharmaSea website – behind login
Will be enhanced with data deposition capabilities and “dereplication”

18. The PharmaSea Website

19. The PharmaSea Website

20. The PharmaSea Website

21. New Repository Architecture doi: 10.1007/s10822-014-9784-5

22. New Repository Architecture

23. Compounds

24. Reactions

25. Analytical data

26. Crystallography data

27. Deposition of Data

28. Extending PharmaSea Site
PharmaSea website will be extended
Spectral data handling: Support Dereplication

29. Identifying novel compounds
Compounds are collected from the ocean
Extraction via chromatography
Analytical sciences including:
UV-Vis data (Lambda-max)
Mass spectrometry (formula/mass)
NMR spectroscopy (HNMR/2D)
Utilized for dereplication,,,

30. Is this already known or not??

31. Identifying novel compounds
4 Me singlets
4 Me doublets
1 OMe singlet
Aromatic protons

32. Identifying novel compounds
2D NMR data will give details regarding substitutions and this information can be used in the dereplication process

33. What we need is… If we could have:
A DB containing known marine natural products
This would give formula and mass for searching
The DB has all spectral data available for each compound
If experimental data are not available then use the compound to COMPUTE spectral features

34. RSC Acquires Marinlit All Marinlit chemical compounds in ChemSpider
Marinlit developers are dereplication experts

35. Structure searchable database
Index literature related to marine natural products: 26K articles and growing
Structure searchable database
Data includes taxonomy, location and literature
“Spectral features” generated algorithmically
Utilize the spectral features for dereplication
MarinLit is ‘article-centric’ and not compound centric. Compounds are only indexed when they are newly discovered, revised, or new to marine.
All compound records link to the paper they were first mentioned. They are not linked to subsequent articles that describe them.

38. PharmaSea Dereplication
Work in progress:
Produce “dereplication widget” to embed in the PharmaSea website
Generate “structure features” file for every new compound deposited to PharmaSea
Ideal would be to utilize spectral data directly to elucidate structures – “Computer Assisted Structure Elucidation”. ACD/Labs….

39. CASE-based Elucidation
Computers can elucidate structures today with greater efficiency and success than many scientists – see Patrick Wheeler’s talk
Natural products specifically can be very challenging and CASE is well-proven
ACD/Labs have delivered their CASE-system (ACD/Structure Eludicator) to the project

40. 1D & 2D NMR Synchronized Processing
The Software displays correlations for assigned spectra and structures, and highlights correlations that are likely to be erroneous.

42. ChemSpider supporting CASE
RSC delivered entire ChemSpider structure dataset for inclusion into the Structure Elucidator software.

43. CASE vs Microscopy? DOI: 10.1002/anie.201203960

44. Single Molecule AFM

45. CASE vs Microscopy? DOI: 10.1002/anie.201203960

46. Next:Tagging Natural Products

47. Next:Tagging Natural Products

48. Next:Tagging Natural Products

49. Next:Tagging Natural Products

50. Future Plans
Roll out tagging on ChemSpider to crowdsource marine natural products subset
Implement tagging for further details onto PharmaSea website
Collaborate with other natural product sources
Mass spectrometry fragmentation prediction

51. Future Plans – MS Fragmenter

52. Future Plans – MS Fragmenter

53. Future Plans

54. To be published: 2015 (RSC)
Modern NMR Approaches To The Structure Elucidation of Natural Products
Volume 1: Instrumentation and Software
Volume 2: Data Acquisition and Applications to Compound Classes
Edited by Antony Williams, RSC, Gary Martin, Merck and David Rovnyak, Bucknell University

55. To be published: 2015 (Springer)
Computer-based Structure Elucidation from Spectral Data
Will include a functional demo version of the ACD/Structure Elucidator software to teach the basic approaches to computer-assisted structure elucidation
Authored by Mikhail Elyashberg, Kirill Blinov and Antony Williams

56. Acknowledgments
Alexey Pshenichnov, Ken Karapapetyan and Valery Tkachenko (RSC – US Cheminformatics)
Marcel Jaspars (University of Aberdeen)
John Blunt and Murray Munro (Marinlit)
Serin Dabb (RSC, Marinlit)
Patrick Wheeler and David Hardy (ACD/Labs)

57. Thank you
ORCID:
Personal Blog:
SLIDES: 57