implementing electronic laboratory notebooks

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IMPLEMENTING ELECTRONIC LABORATORY NOTEBOOKS TO IMPROVE THE EFFICIENCY OF PRE-CLINICAL DRUG DISCOVERY Sheraz Gul Vice President and Head of Biology, European ScreeningPort GmbH

The pre-clinical phase of drug discovery spans a period in the region of five years and requires contributions from multi-disciplinary teams often working at different sites. These teams can generate significant amounts of data which are processed using standard as well as specialist software. The recording of a substantial amount of project related experimental work has historically been performed using paper-based laboratory notebooks completed manually with all files usually being stored locally.

be achieved upon implementing an eLNB in pre-clinical drug discovery.

The stages of small molecule pre-clinical drug discovery and associated data that is generated Within the well defined stages of pre-clinical drug discovery, there are an ever increasing

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This scenario poses a variety of issues such

in industry and academia. Such software

number of reagents, methods and technologies

as delayed access to important information to

allows the documentation of experimental data

available to improve their productivity and

the project team members which could

and its sharing within the multi-disciplinary

efficiency. The gene-to-target stage involves the

ultimately reduce its efficiency and thus

research team and would be expected to

identification of a target implicated in a disease

increase the time taken to complete the

improve data integrity, reduce the time

process and the subsequent generation of

project. These paper-based notebooks are now

to complete the project and improve

biological reagent/s that contain the target

being replaced by an electronic laboratory

communication. This article discusses some

protein and in some cases also its protein

notebook (eLNB) within research laboratories

of the advantages that would be expected to

substrate1,2. These activities will generate data in

European Pharmaceutical Review Volume 16 | Issue 6 | 2011

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ELNs a variety of forms such as gene sequence data in

signal/background), determine the presence of

identify assay format specific false positives

text files, agarose gel and SDS-PAGE gel images,

microtitre plate edge effects (which are

together with secondary assays (typically cell

Western blot images and protein purification

particularly prominent in cell based assays),

based assays). Confirmed hits would then be

elution traces, all of which are analysed using

normalise the data (using the high and low

assessed in dose-response experiments in the

suitable software to provide a quantitative

primary target specific assay in order to allow

output. The biological reagent/s can sub -

their potencies to be determined. Although

sequently be utilised to develop assays to

these activities would be performed upon a

monitor target activity and these are usually

smaller number of compounds than the HTS

compatible with microtitre plates of various

campaign itself, each compound would be

densities3. These assays often make use of the

tested at a number of concentrations to provide

target protein of interest in isolation (e.g. a

preliminary structure-activity-relationships.

biochemical assay) or in a more complex setting

All the raw data files would be archived and

(e.g. cell based assay)4,5. Having developed an

the processed data available to the project team.

appropriate assay, it is subsequently utilised in a

In order to select compounds for further study,

high throughput screening (HTS) campaign

they would be annotated with additional

against libraries of small molecules in order to

selectivity and physicochemical data after which

identify those that modulate the activity of the

an informed decision can be made to select

target in the desired manner. Upon completion

appropriate compounds for progression. From

of the HTS campaign, those compounds that

the initial list of validated hit molecules, a

give suitable activity are first re-tested in a confirmation assay. Depending upon the numbers of compounds that are evaluated, these activities could generate a vast amount of data in terms of the numbers of text files

“ The use of an electronic

laboratory notebook (eLNB) is becoming commonplace in drug discovery ”

containing the raw data from a microtitre plate-

relatively small number are usually considered for further exploration during the Hit-to-Lead (H2L) phase and subsequently the Lead-toCandidate phase. During both these phases, synthesis of new compounds would be undertaken with a view to (i) optimising their

reader. These files are subsequently processed

controls) and calculate hit rates6. The activity of

potency at the target of interest, (ii) improving

using suitable software to calculate top level

the hits would be determined in a confirmation

their selectivity and liability profile, (iii)

microtitre plate level statistics (Z' and

assay as well as a suitable counter assay to

increasing the synthetic yield, (iv) search

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Enabling Science

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ELNs databases for the activities of the compounds

individuals may no longer be employed within

proteins and data visualisation18. However, this

against other targets, (v) determine patentability

the same department or organisation.

option is in most cases not possible due to the

and competitor activity for compounds and

lack of expertise and the significant amount of

The role of an electronic notebook in pre-clinical drug discovery

time that would be required to build such

acceptable physicochemical and in vivo profile (e.g. solubility, stability in aqueous

The recording of pre-clinical drug discovery

of an eLNB from a vendor would be optimal.

solution and human plasma, suitable in vivo

related information has for a considerable

The use of an eLNB would be expected to

pharmacokinetics, Absorption, Distribution,

time been documented by scientists within

maximise the use of the data generated as

Metabolism and Excretion (ADME) properties).

organisations in paper-based notebooks which

described above and allow its management in a

The time to take a project from the cloning of a

are completed manually 10,11. Subsequent to

consistent manner thus saving the valuable

target protein to the successful development of

completion of the paper-based notebook, it

time of scientists19.

a clinical candidate molecule can take five years

would be scanned and stored in a database.

Pre-clinical drug discovery is a lengthy

However, text recognition would not be possible

process and requires the input of multi-

upon scanning and therefore these would have

disciplinary teams which are often based

limited use when searching for specific

on multiple sites. The documentation of

information. The use of an electronic laboratory

experimental details, raw data and results are

notebook (eLNB) is becoming commonplace in

now being performed using eLNBs. These allow

drug discovery, especially within the large

for improved data integrity, enable immediate

target and (vi) ensuring the compounds have an

“ The use of an eLNB would be

expected to maximise the use of the data generated ” to complete and will involve individuals within

pharmaceutical organisations, biotechs and

an organisation as well as external organisations

academia12. These are available from a number

7-9

software. Therefore, in most cases the purchase

“ The documentation of experimental details, raw data and results are now being performed using eLNBs ”

to whom work may be contracted . The data

of suppliers and there are many types

generated during the various studies are likely to

available for purchase13-17. An alternative is to

be acquired and processed using specialised

design and develop a custom eLNB and this is

software and the results collated using more

exemplified by OSIRIS (developed at Actelion

general software for circulation to the project

Ltd) which covers biology and chemistry

team and discussed at regular project meetings.

related aspects of pre-clinical drug discovery.

It is critical that the experimental protocols, raw

Additional cheminformatics functionalities

archiving and dissemination of the experimental

and processed data are archived in a clear

included within software are physicochemical

protocols and results and thus improve the

manner so that it can be fully searched and

property prediction, comparisons of 3D-

overall productivity of an organisation.

specific information retrieved even when

pharma cophores, docking of ligands into

Additional benefits of implementing an eLNB include the potential to track projects, make

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searches for specific information and generate notebook in a bioanalytical laboratory. Bioanalysis. 2011, 3, 1457-1470 11. Wright JM. Make it better but don't change anything. Autom Exp. 2009, 1, 1-3.

reports without the need to contact individual team members, increase productivity, ensure regulatory compliance and protect intellectual

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property. The eLNB may be web based and

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portable. Although initial training would be

14. Taylor KT. The status of electronic laboratory notebooks for chemistry and biology. Curr Opin Drug Discov Devel. 2006, 9, 348-353 15. Goddard NH, Macneil R, Ritchie J. eCAT: Online electronic lab notebook for scientific research. Autom Exp. 2009, 1, 1-7 16. Khan AM, Hahn JD, Cheng WC, Watts AG, Burns GA. NeuroScholar's electronic laboratory notebook and its application to neuroendocrinology. Neuroinformatics. 2006, 4, 139-162 17. Sakai H, Aoyama T, Yamaji K, Usui S. Concierge: personal database software for managing digital research resources. Front Neuroinform. 2007, 1, 1-6 18. Sander T, Freyss J, von Korff M, Reich JR, Rufener C. OSIRIS, an entirely in-house developed drug discovery informatics system. J Chem Inf Model. 2009, 49, 232-246 19. Zeng J, Hillman M, Arnold M. Impact of the implementation of a well-designed electronic laboratory notebook on bioanalytical laboratory function. Bioanalysis. 2011, 3, 1501-1511

therefore be accessed remotely making it fully necessary to become familiar with the eLNB, the return on investment would be rapid.

BIOGRAPHY

Sheraz Gul is Vice President and Head of Biology at European ScreeningPort, Hamburg, Germany. He is responsible for the management and development of Medium and High Throughput Screening activities for academic partners across Europe. He has 12 years research and development experience in both academia (University of London) and industry (GlaxoSmithKline Pharmaceuticals). This has ranged from the detailed study of catalysis by biological catalysts (enzymes and catalytic antibodies) to the design and development of assays for High Throughput Screening for the major biological target classes. He is the co-author of numerous papers, chapters and the Enzyme Assays: Essential Data handbook.