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

The Grid in a Combinatorial Laboratory

Jeremy FreyDepartment of Chemistry

University of Southampton

Page 2: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

•Bristol •Chemistry

•ECS

•Stats

•Chemistry

•Combi •Centre

•Southampton •IUPAC•RSC

•IBM

•CCDCCCDC

•PfizerPfizer

•IT •Innovation

•CombCombeeChemChem

•GSKGSK

•AZAZ

•NCS

Page 3: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

Design

AutomationAnalysis

Structures

Models

Properties

Experiment

Page 4: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

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.

Page 5: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

2 polymorphs5 organic salts 12 co-crystals2 polymorphs5 organic salts 12 co-crystals

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.

Page 6: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

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.

Page 7: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

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

Page 8: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

National Crystallography Service: NCS

SYNTHON Project

Voronoi Project

Single Crystal Structure Determination

Powder Diffraction

Single Molecule Shape Determination Property Prediction Services

Structure DeterminationServices

Page 9: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

user

NCS

technicianAudio

VNC monitor control

VNC ideal for connecting existing programs

technician

LAB

Office

VNC ControlAudio

Page 10: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

VNC Web Service

VNC Client

PC

Equipment

PC

VNC Server

Firewalls

Web ServiceProxy

Tunnel Endpoint

SOAPSOAPRFB

Tunnel RFB over SOAP Equipment

PC

VNC Server

Page 11: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

Page 12: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

NCS Lab Service

Samples andSchedules

StatusMonitor

Collaboratory Interface Data Access Interface

Proxy Proxy Proxy

ControlGUI

(FilteredVNC)

Chat AudioRaw

ImagesResultsAccess

StructAccess

Schedules

SampleManage-

ment

ScheduleManage-

ment

Raw Data(Files)

ProcessedData (DB)

StructureData (DB)

Admin

Auth

Scheduling Expt Control HKL Calculation Struct Calc

UI

Middleware

Backend

Control

Page 13: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

NCS Scenario (1)

Send sample to NCS

Receive confirmation(sample received)

Receive notification(sample scheduled)

Receive sample

Enter into Sample DB

Send confirmation(sample received)

Setup schedule forfollowing day

Notify user(sample scheduled)

Prepare sample

Previous experimentfinishes

Receive notification(sample preparation

underway)

Start new experimentReceive notification(experiment setup

started)

End User Lab Technician

Monitor experimentStart conference

(text / audio / vnc)

Page 14: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

Sample Processing(X-ray Experiment (1))

Scheduled

Add to queue

Scheduled:sample prep

underway

Update schedule

Scheduled:sample prepared

Running:expt setup

started

Running:unit cell:

collecting scanx (of y)

Running:expt setupcompleted

Running:unit cell:

collected scanx (of y)

Running:unit cell:

calculatingunit cell

Running:unit cell:

generating imagex (of y)

Running:unit cell: image

x (of y) available

Running:unit cell:

calculationcomplete

Running:unit cell:

unit cell dataavailable

Start sample preparation

Finish sample preparation

Setup experiment(mount sample,create directory)

Collect scan

Scans complete.Start unit cell calculation

Finish unit cellcalculation

Start unit celldetermination

Start imagegeneration

Finish imagegeneration.

Publish image

Publish unit celldata

Start next scan

Discard unit cell

Running:crystal

discarded

Running:sample prep

underway

Running:sample prepared

Start sample preparation

Finish sample preparation

Discard crystal

Start newexperiment

Startdata collection

Initiated by Lab Technician

Executed automatically

Key

New samplereceived

Sample datastored

(pendingschedule)

Unpack sample,process and store data

Receive new sample

Start

Page 15: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

User Authorisation(X-ray Experiment)

(Setup running)can request statuscan monitor status

can connect to conferencecan download images

(Prep new crystal)can request statuscan conference?

can monitor?

(Prev. expt finishes)Start new expt (launch control GUI),

notify user

Authenticatedusers

Revoke users

Discard crystal

Discard unit cell

New crystal ready

(New)can send sample

(Pending schedule)can request status

(Scheduled)can request statuscan monitor status

(Ready to start)can request statuscan monitor status

Unpack, enter data,send confirmation

Schedule for tomorrow,notify user

Sample prepared,notify user

(Data collection)can request statuscan monitor status

(Raw data available)can request statuscan download HKL

(Structure available)can request statuscan download HKL

can download structure

(Finished)

Experiment finished + postprocess completed(HKL available)

Structure determined(structure data available)

Publish data?Archive data?

Timeout?

Setup completed

Abort

Page 16: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

Portal Access

Page 17: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

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

Page 18: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

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)

Page 19: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

Laser x-ray single molecule scattering

High Power Laser X-Ray Target

Interlock Systems

Safety

Page 20: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Analysis

Structural Similarity & Difference

Graham Tizard & Thomas Gelbrich

Page 21: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

Develop process on

few

Apply to the

whole library

Synthesis, analysis,

measurements

Design of experimen

ts

Page 22: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

Full combinatorial space

polymorphs

Salts

Page 23: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

Influence of electrostatic potentials on the formation of a non-centro-symmetric member of a set of polymorphic crystal structures

Polymorphic Families G. Tizard

Page 24: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

Unit cell parameters and isostructurality

Spgr. a (Å) b (Å) c (Å)

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

Page 25: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

I3BPMe3 Cl3BNMe2F Cl3BNMe2Cl I3BAsMe3

Me3AlNMe3 Me2IAlNMe3 Me3GaPMe3 (BH4)3AlAsMe3

Page 26: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

Unit cell parameters and isostructurality

Spgr. a (Å) b (Å) c (Å)

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

Check the atomic coordinates!

Page 27: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

Synthon

Comparison

Molecules

Crystal Structures

A

A

Space groupUnit cellAtom lis

B

B

Space groupUnit cellAtom list

Conventional crystal structure parameters do not support the analysis of packing similarities!

Page 28: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

Comparison

Molecules

Crystal Structures

A

A

Space groupUnit cellAtom list

Alternative parameters

B

B

Space groupUnit cellAtom list

Alternative parameters

Analysis

Synthon

Page 29: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

Sulfathiazole

T. Gelbrich: The SYNTHON Project 1/3

Polymorph III IV V

Space Group P21/c P21/c P21/n

Unit Cell a[Å] 17.570 8.193 10.774

b[Å] 8.574 8.538 8.467

c[Å] 15.583 15.437 11.367

beta[ ] 112.93 94.01 91.65

Z‘ 2 1 1

Page 30: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

SN

N

O

O

R1

R2

H

Prototype

Page 31: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

SN

N

O

O

R1

R2

H

Prototype

Page 32: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

SN

N

O

O

R1

R2

H

Prototype

Page 33: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

0D:

Dimers

I = (pseudo*)- inversion

R = (pseudo*)- rotation

I I I

I

I

I*II

I I*II

III

I*II

II

I

II

II

II

II

I

I R*

I

I

I I

R*

R*,R*

II

R*

II

I

I

I

I I

II / / R*

II

II / III /

II / I / R*

I /D / IR* / II

I

I

I

Page 34: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Type A Type B

A A

AA A

A

A

A

A AB AB

AB AB

A

A

A

1D:

Chains

AB

AB ABAB AB

A A A

Page 35: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

The Synthons of Sulfathiazole III, IV, V

I A single sheet 2D

II AB double sheet 2D III AA double sheet 2D

Sulfathiazole

V III IV

Polymorphs

ABABABAB AABBAABB AAAAAAA

Page 36: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Back to the Laboratory

If information is destined for the Grid then this should be implicit from the beginning.

Page 37: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

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

Page 38: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

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

Page 39: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

Metadata

material Batch no.Identifier Supplier db

process

measureLab database Safety db

In the Grid world the databases are distributed not local copies

Need a language to convey all details in a standard mannerXML cf CatML description of catalysts - IUPAC role

Page 40: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

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.

Page 41: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

0.1 0.2 0.3 0.4 0.50.4

0.6

0.8

1.0

1.2

1.4

1.6

4-nitrobenzo-15-crown-5 DCE | Water

Crown

Na Complex

I SP

/ IP

P

E / V

O

O

O

O

O

N O 2

O

O

O

O

O

N O 2

K +K +

D 3 d D 3 d

Second Harmonic Generation a liquid liquid interfaces underelectrochemical control

Page 42: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

0

2

4

6

8

10

-0.5 0 0.5 1 1.5 2

-1

0

1

2

3

4

5

6

7

-0.5 0 0.5 1 1.5 2

01234

5678

-0.5 0 0.5 1 1.5 2

Polarisation dependence of SHG signal

0

20

40

60

80

100

120

140

160

180

Page 43: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

0.20.30.40.50.60.70.80.9

11.1

1 83 165

247

329

411

493

575

657

739

821

903

985

1067

1149

1231

1313

1395

1477

1559

1641

1723

1805

1887

1969

0

0.2

0.4

0.6

0.8

1

1.2

1 15 29 43 57 71 85 99 113

127

141

155

169

183

197

211

225

239

Raw laser signal

Page 44: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

High throughput – close coupling

•Design •Analysis

•Experiments•Statistics using R•Open Source•Works with XML

Databases

Page 45: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

Journals: Publication @ source

JournalJournal

Materials

Database

Multimedia

Laboratory Data

Paper

“Full” record

Page 46: The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton.

Reality Grid Workshop18 June 2003

Jeremy Frey, Department of Chemistry University of

Southampton

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