The Grid in a Combinatorial Laboratory
Jeremy FreyDepartment 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
Reality Grid Workshop18 June 2003
Jeremy Frey, Department of Chemistry University of
Southampton
Design
AutomationAnalysis
Structures
Models
Properties
Experiment
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.
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.
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.
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
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
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
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
Reality Grid Workshop18 June 2003
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
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)
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
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
Reality Grid Workshop18 June 2003
Jeremy Frey, Department of Chemistry University of
Southampton
Portal Access
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
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)
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
Analysis
Structural Similarity & Difference
Graham Tizard & Thomas Gelbrich
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
Reality Grid Workshop18 June 2003
Jeremy Frey, Department of Chemistry University of
Southampton
Full combinatorial space
polymorphs
Salts
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
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
Reality Grid Workshop18 June 2003
Jeremy Frey, Department of Chemistry University of
Southampton
I3BPMe3 Cl3BNMe2F Cl3BNMe2Cl I3BAsMe3
Me3AlNMe3 Me2IAlNMe3 Me3GaPMe3 (BH4)3AlAsMe3
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!
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!
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
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
SN
N
O
O
R1
R2
H
Prototype
SN
N
O
O
R1
R2
H
Prototype
SN
N
O
O
R1
R2
H
Prototype
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
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
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
Back to the Laboratory
If information is destined for the Grid then this should be implicit from the beginning.
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
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
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
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.
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
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
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
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
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
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