The Grid in a Combinatorial Laboratory

1. The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton

2. IUPAC • RSC • CombeChem • IT • Innovation • IBM • NCS • CCDC • Bristol • Chemistry • ECS • Chemistry • Pfizer • Combi • Centre • Stats • GSK • AZ • Southampton Jeremy Frey, Department of Chemistry University of Southampton

3. Properties Models Design Structures Experiment Automation Analysis Jeremy Frey, Department of Chemistry University of Southampton

4. Pharmaceutical SaltsS.C. Ward • Salts allow the properties of the solid forms to be modified without altering the biochemical properties of a drug. • Selecting the best salt form for an ionisable drug is now of paramount importance in the pharmaceutical development of new chemical entities. • No accepted procedure for selecting such a form during the drug development process. Jeremy Frey, Department of Chemistry University of Southampton

5. One such parent acid is succinic acid, it is a pharmaceutically acceptable acid and can exist in two polymorphic forms. In each case the succinic acid molecules are linked into zigzag chains by strong O-H….O hydrogen bonds. Jeremy Frey, Department of Chemistry University of Southampton

6. Salt Screen • More often than not, salts selected on a practical basis, such as previous experience with the salt type, ease of synthesis, percentage yield, etc. • A detailed systematic study of organic salt formation is required to enhance our understanding of all the factors that affect salt formation. • The process of identifying chemical space begins with the choice of descriptors. Jeremy Frey, Department of Chemistry University of Southampton

7. Salt Formation SpaceS.C. Ward, D. Woods, S.M. Lewis, M.B. Hursthouse • A variety of traditional descriptors have been investigated along with BCUT descriptors. • Use Design of Experiments (DoE) statistical techniques to ensure coverage of the space with a reasonable size sample. • Still lots of experiments • Need high throughput automated crystalography Jeremy Frey, Department of Chemistry University of Southampton

8. Structure Determination Services National Crystallography Service: NCS Single Crystal Structure Determination Powder Diffraction SYNTHON Project Voronoi Project Single Molecule Shape Determination Property Prediction Services Jeremy Frey, Department of Chemistry University of Southampton

9. Office technician Audio VNC Control VNC monitor NCS control user technician Audio LAB VNC ideal for connecting existing programs Jeremy Frey, Department of Chemistry University of Southampton

10. Equipment Equipment Tunnel RFB over SOAP PC PC PC VNC Client VNC Server VNC Server RFB SOAP SOAP Tunnel Endpoint Web ServiceProxy Firewalls VNC Web Service Jeremy Frey, Department of Chemistry University of Southampton

11. Jeremy Frey, Department of Chemistry University of Southampton

12. NCS Lab Service Jeremy Frey, Department of Chemistry University of Southampton

13. NCS Scenario (1) Jeremy Frey, Department of Chemistry University of Southampton

14. Sample Processing(X-ray Experiment (1)) Jeremy Frey, Department of Chemistry University of Southampton

15. User Authorisation(X-ray Experiment) Jeremy Frey, Department of Chemistry University of Southampton

16. Portal Access Jeremy Frey, Department of Chemistry University of Southampton

17. Use of Certificates • The Certificate performs two main functions: • secure communication through encryption using its public key • positive identification of the Subscriber through the identity assertion • the DN in the certificate is used as an identifier for the Subscriber in the sample tracking database • The Certificate’s integrity is vouched for through the the CA’s signature • The Certificate is distributed to all parties with whom its owner wishes to communicate Jeremy Frey, Department of Chemistry University of Southampton

18. Remote interaction • Remote control of equipment • Interaction with people & equipment • Security Issues • Authentication and Authorisation within and across organisations • Safety Critical Systems • External & Internal control of systems can lead to safety conflicts • Mission critical software (avoid at this stage) Jeremy Frey, Department of Chemistry University of Southampton

19. Laser x-ray single molecule scattering High Power Laser X-Ray Target Interlock Systems Safety Jeremy Frey, Department of Chemistry University of Southampton

20. Analysis Structural Similarity & Difference Graham Tizard & Thomas Gelbrich

21. Develop process on few Apply to the whole library Synthesis, analysis, measurements Design of experiments Jeremy Frey, Department of Chemistry University of Southampton

22. polymorphs Salts Full combinatorial space Jeremy Frey, Department of Chemistry University of Southampton

23. Polymorphic Families G. Tizard Influence of electrostatic potentials on the formation of a non-centro-symmetric member of a set of polymorphic crystal structures Jeremy Frey, Department of Chemistry University of Southampton

24. Unit cell parameters and isostructurality Jeremy Frey, Department of Chemistry University of Southampton

25. Jeremy Frey, Department of Chemistry University of Southampton

26. Unit cell parameters and isostructurality Check the atomic coordinates! Jeremy Frey, Department of Chemistry University of Southampton

27. A B Molecules A B Crystal Structures Synthon Space groupUnit cellAtom lis Space groupUnit cellAtom list Comparison • Conventional crystal structure parameters • do not support the analysis • of packing similarities! Jeremy Frey, Department of Chemistry University of Southampton

28. A B Molecules A Synthon B Crystal Structures Space groupUnit cellAtom list Space groupUnit cellAtom list Analysis Alternative parameters Alternative parameters Comparison Jeremy Frey, Department of Chemistry University of Southampton

29. Sulfathiazole Jeremy Frey, Department of Chemistry University of Southampton T. Gelbrich: The SYNTHON Project 1/3

30. Prototype

31. Prototype

32. Prototype

33. 0D: Dimers I I I I I I I I II I* I = (pseudo*)- inversion R = (pseudo*)- rotation I I I II I* II I* I I I II I II I II II II II R* R* II II I R*,R* II II / / R* II / I II / II / I / R* I /D / I R* / II I I I R* I I

34. 1D: Chains A A A A A Type A Type B A A A A A AB AB AB A AB AB AB AB AB AB A A A A

35. The Synthons of Sulfathiazole III, IV, V Sulfathiazole Polymorphs V III IV ABABABAB AABBAABB AAAAAAA II AB double sheet 2D III AA double sheet 2D I A single sheet 2D Jeremy Frey, Department of Chemistry University of Southampton

36. Back to the Laboratory If information is destined for the Grid then this should be implicit from the beginning.

37. Pervasive Computing and the Laboratory Grid • Automatic capture of metadata • Sample tracking • Conditions monitored • Data recorded • Relational Databases • common in industrial research not so in university • Room/People/Experiment • Types of information Jeremy Frey, Department of Chemistry University of Southampton

38. Databases • Database will become the key method of handling all data • Metadata must be generated at inception and added as data traverses the workflow • Version control, audit and backup handled at the database level. • Change in the outlook of most bench chemists Jeremy Frey, Department of Chemistry University of Southampton

39. Metadata In the Grid world the databases are distributed not local copies measure Lab database Safety db process Batch no. material Identifier Supplier db Need a language to convey all details in a standard mannerXML cf CatML description of catalysts - IUPAC role Jeremy Frey, Department of Chemistry University of Southampton

40. Second Harmonic Generation • Used to study liquid surfaces and liquid-liquid interfaces • Model membranes for industrial and biochemical processes. • Used to develop the tight coupling of design – experiment – analysis. • Results of one experiment modify the procedure used in the next. Jeremy Frey, Department of Chemistry University of Southampton

41. Second Harmonic Generation a liquid liquid interfaces underelectrochemical control Jeremy Frey, Department of Chemistry University of Southampton

42. 180 160 140 120 100 80 60 40 20 0 Polarisation dependence of SHG signal Jeremy Frey, Department of Chemistry University of Southampton

43. Raw laser signal Jeremy Frey, Department of Chemistry University of Southampton

44. High throughput – close coupling • Design • Analysis • Experiments • Statistics using R • Open Source • Works with XML • Databases Jeremy Frey, Department of Chemistry University of Southampton

45. Database Journal Journal Paper Laboratory Data Materials Multimedia Journals: Publication @ source “Full” record Jeremy Frey, Department of Chemistry University of Southampton

46. People • Mike Hursthouse, Thomas Gelbrich, Graham Tizard, Susana Ward, Mike Surridge, Sue Lewis, Dave Woods, Simon Coles, Mark Light, Lefteris Danos, Steve Taylor, Ken Meacham, Ann Bingham, Dave de Roure, Graham Smith, Hugo Mills, Alan Welsh Jeremy Frey, Department of Chemistry University of Southampton