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

Jan 04, 2016

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  • The Grid in a Combinatorial LaboratoryJeremy FreyDepartment of ChemistryUniversity of Southampton

  • Bristol ChemistryECSStatsChemistryCombi CentreSouthamptonIBMCCDCPfizerIT InnovationCombeChemGSKAZNCS

  • DesignAutomationAnalysisStructuresModelsPropertiesExperiment

  • Comb-e-Chem VisionA Pervasive Grid-Based e-Science EnvironmentStructures DBProperties DBSimulation andcalculationStructure + PropertiesKnowledge + Prediction

  • Pharmaceutical SaltsS.C. WardSalts 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.

  • 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.

  • Salt ScreenMore 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.

  • 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 experimentsNeed high throughput automated crystalography

  • National Crystallography Service: NCSSYNTHON ProjectVoronoi ProjectSingle Crystal Structure DeterminationPowder DiffractionSingle Molecule Shape Determination Property Prediction ServicesStructure DeterminationServices

  • userNCStechnicianAudioVNC monitorcontrolVNC ideal for connecting existing programstechnicianLABOfficeVNC ControlAudio

  • VNC Web Service

  • NCS Lab Service

  • NCS Scenario (1)

  • Sample Processing(X-ray Experiment (1))

  • User Authorisation(X-ray Experiment)

  • Portal Access

  • Public / Private Key EncryptionA subscriber generates a key paircomprising a complimentary private and public keyThe private key is kept strictly privateThe public key is distributed to anyone its owner wishes to communicate with

    When the public key is used to encrypt data, only the private key may decrypt this data

  • CertificatesA certificate comprises:a public keyan identity assertionfor Combechem, this is in the form of an X.500 Distinguished Name (DN)a signature of a trusted authority asserting: the validity of the public key the validity of the identity assertionthat the public key is the one generated by the person represented in the identity assertionfor Combechem, this trusted authority is the Combechem Certificate Authority (CA)

  • Use of CertificatesThe Certificate performs two main functions:secure communication through encryption using its public keypositive identification of the Subscriber through the identity assertionthe DN in the certificate is used as an identifier for the Subscriber in the sample tracking databaseThe Certificates integrity is vouched for through the the CAs signatureThe Certificate is distributed to all parties with whom its owner wishes to communicate

  • Remote interactionRemote control of equipmentInteraction with people & equipmentSecurity IssuesAuthentication and Authorisation within and across organisationsSafety Critical SystemsExternal & Internal control of systems can lead to safety conflictsMission critical software (avoid at this stage)

  • Laser x-ray single molecule scatteringHigh Power LaserX-Ray TargetInterlock SystemsSafety

  • AnalysisStructural Similarity & DifferenceGraham Tizard & Thomas Gelbrich

  • Develop process on fewApply to the whole librarySynthesis, analysis, measurementsDesign of experiments

  • Full combinatorial spacepolymorphsSalts

  • Influence of electrostatic potentials on the formation of a non-centro-symmetric member of a set of polymorphic crystal structures Polymorphic FamiliesG. Tizard

  • Unit cell parameters and isostructurality

    Spgr.

    a ()

    b ()

    c ()

    I3B

    (PMe3

    Pnma

    13.033

    11.636

    7.282

    Cl3B

    (NMe2F

    Pn21a

    10.744

    10.108

    6.449

    Cl3B

    (NMe2Cl

    Pnma

    11.626

    9.984

    6.515

    I3B

    (AsMe3

    Pnma

    13.113

    11.733

    7.387

    Me3Al

    (NMe3

    Pnma

    12.204

    10.732

    7.224

    Me2IAl

    (NMe3

    Pnma

    12.590

    10.750

    7.580

    Me3Ga

    (PMe3

    Pnma

    12.704

    11.174

    7.806

    (BH4)3Al

    (NMe3

    Pnma

    12.880

    11.400

    7.150

  • I3B(PMe3

    Cl3B(NMe2F

    Cl3B(NMe2Cl

    I3B(AsMe3

    Me3Al(NMe3

    Me2IAl(NMe3

    Me3Ga(PMe3

    (BH4)3Al(AsMe3

  • Unit cell parameters and isostructuralityCheck the atomic coordinates!

    Spgr.

    a ()

    b ()

    c ()

    I3B

    (PMe3

    Pnma

    13.033

    11.636

    7.282

    Cl3B

    (NMe2F

    Pn21a

    10.744

    10.108

    6.449

    Cl3B

    (NMe2Cl

    Pnma

    11.626

    9.984

    6.515

    I3B

    (AsMe3

    Pnma

    13.113

    11.733

    7.387

    Me3Al

    (NMe3

    Pnma

    12.204

    10.732

    7.224

    Me2IAl

    (NMe3

    Pnma

    12.590

    10.750

    7.580

    Me3Ga

    (PMe3

    Pnma

    12.704

    11.174

    7.806

    (BH4)3Al

    (NMe3

    Pnma

    12.880

    11.400

    7.150

  • SynthonComparisonMolecules Crystal Structures AA Space groupUnit cellAtom lisBB Space groupUnit cellAtom listConventional crystal structure parameters do not support the analysisof packing similarities!

  • ComparisonMolecules Crystal Structures AA Space groupUnit cellAtom listAlternative parametersBB Space groupUnit cellAtom list Alternative parameters

    AnalysisSynthon

  • SulfathiazoleT. Gelbrich: The SYNTHON Project 1/3

    Polymorph

    III

    IV

    V

    Space Group

    P21/c

    P21/c

    P21/n

    Unit Cell a[]

    17.570

    8.193

    10.774

    b[]

    8.574

    8.538

    8.467

    c[]

    15.583

    15.437

    11.367

    beta[(]

    112.93

    94.01

    91.65

    Z

    2

    1

    1

  • Prototype

    I

    Br

    Cl

    Me

    H

    F

    Cl

    Br

    I

    CF3

    Me

    H

    NH2

    NHCHOMe

    NHCHO

  • Prototype

    I

    Br

    Cl

    Me

    H

    F

    Cl

    Br

    I

    CF3

    Me

    H

    NH2

    NHCHOMe

    NHCHO

  • Prototype

    I

    Br

    Cl

    Me

    H

    F

    Cl

    Br

    I

    CF3

    Me

    H

    NH2

    NHCHOMe

    NHCHO

  • 0D:DimersI = (pseudo*)- inversionR = (pseudo*)- rotationIIIIII*IIII*IIIIII*IIIIIIIIIIIIIII R*IIII R*R*,R*II R*IIIIIIIII / / R*II II / III /II / I / R*I /D / IR* / IIIII

    I

    Br

    Cl

    Me

    H

    F

    Cl

    Br

    I

    CF3

    Me

    H

    NH2

    NHCHOMe

    NHCHO

  • Type A Type B A A AA A A A AA AB ABAB AB A A A1D:Chains ABABABABAB A A A

    I

    Br

    Cl

    Me

    H

    F

    Cl

    Br

    I

    CF3

    Me

    H

    NH2

    NHCHOMe

    NHCHO

  • The Synthons of Sulfathiazole III, IV, V

  • Back to the LaboratoryIf information is destined for the Grid then this should be implicit from the beginning.

  • Pervasive Computing and the Laboratory GridAutomatic capture of metadataSample trackingConditions monitoredData recordedRelational Databases common in industrial research not so in universityRoom/People/ExperimentTypes of information

  • DatabasesDatabase will become the key method of handling all dataMetadata must be generated at inception and added as data traverses the workflowVersion control, audit and backup handled at the database level.Change in the outlook of most bench chemists

  • MetadatamaterialBatch no.IdentifierSupplier dbprocessmeasureLab databaseSafety dbIn the Grid world the databases are distributed not local copiesNeed a language to convey all details in a standard manner XML cf CatML description of catalysts - IUPAC role

  • Second Harmonic GenerationUsed to study liquid surfaces and liquid-liquid interfacesModel 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.

  • Second Harmonic Generation a liquid liquid interfaces under electrochemical control

  • Polarisation dependence of SHG signal

    Chart2

    1.13639635061.3415012084

    0.06461227590.0498723763

    0.34609574570.4226369724

    1.84913751631.7729263209

    3.87044763863.2214381527

    5.46423264224.4741087478

    5.88474281086.0150738739

    4.93521676325.3737383604

    3.05994828982.7420423518

    1.13639635061.6095912535

    0.06461227590.1541410225

    0.34609574570.1783290684

    Sheet1

    REIMREIM

    a10.25Chi 1(zzz)8.16488070819712+24.1562658990699i8.164880708224.1562658991A0.58343516242.768235063

    a2-0.22Chi 2(zxx)-1.23606318

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