Using Informatics to Streamline Pre-Clinical Drug Discovery

Implementing an Electronic Laboratory Notebook (ELN) in pre-clinical drug discovery?

sheraz-gul
Contributor: Sheraz Gul
Posted: 08/28/2012
The pre-clinical phase of drug discovery  involves many years of research being conducted by multi-disciplinary teams. These teams will generate significant amounts of data which are processed using standard as well as specialist software.
 
Traditionally, most of the information generated would typically be recorded using paper-based laboratory notebooks (ELN) and the associated electronic data is stored locally in a personalised format.
 
The Electronic Laboratory Notebook (ELN) is now extensively implemented within industry and academia and this allows documentation of experimental data in a manner that can be accessed by all project team members.
 
Here is a summary of the various phases of pre-clinical drug discovery, the types of information that are typically generated and how an ELN can improve data integrity, ensure rapid dissemination of important results and reduce the cycle-time for project completion.
 
  • The gene-to-target stage involves the identification of a target implicated in a disease process and the subsequent generation of key biological reagents. These activities will generate data in a variety of formats such as gene sequence data in text files, agarose, SDS-PAGE and Western blot images and protein purification elution traces.
     
  • The assay development, screening and Hit validation stage requires the biological reagents that have been generated to be utilised to develop suitable assays to monitor target activity in microtitre plate format. These assays often make use of the target protein of interest in isolation (e.g. a biochemical assay) or in a more complex setting (e.g. cell based assay). These activities will generate be-spoke data sets, often unique to the target being investigated. Having developed an appropriate assay, it is can subsequently be utilised in a screening campaign against libraries of small molecules in order to identify those that modulate the activity of the target in the desired manner. Upon completion of the screening campaign, the activities of the Hits can be determined in a confirmation assay as well as a suitable counter assay to identify assay format specific false positives. Confirmed Hits can then be assessed in dose-response experiments in the initial screening assay in order to allow their potencies to be determined. Although these latter activities are performed upon a smaller number of compounds than the screening campaign itself, each compound can be tested at a number of concentrations to provide preliminary structure-activity-relationships. Depending upon the numbers of compounds that are evaluated, these activities can generate a vast amount of data. All the raw data files are typically  archived and the processed data made available to the project team.
     
  • The Hit-to-Lead and Lead-to-Candidate stages involve a detailed analysis of the initial list of validated Hit molecules, ultimately leading to the synthesis of new compounds in order to optimise their potency at the target of interest, improving their selectivity and liability profile, ensuring the compounds have an acceptable physicochemical and in vivo profile (e.g. solubility, stability in aqueous solution and human plasma, suitable in vivo pharmacokinetics, Absorption, Distribution, Metabolism and Excretion properties), increasing the synthetic yield, searching databases for the activities of the compounds against other targets, determining their patentability and any competitor activity.

Pre-clinical drug discovery is a lengthy process and requires the input of multi-disciplinary teams which are often based on multiple sites. The documentation of experimental details, raw data and results are increasingly being performed using an ELN. This allows for improved data integrity, immediate archiving and dissemination of information and results in an improvement in the overall productivity of an organisation. Additional benefits of implementing an ELN include the potential to track projects, make searches for specific information and generate reports without the need to contact individual team members, ensure regulatory compliance and protect intellectual property.

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sheraz-gul
Contributor: Sheraz Gul
Posted: 08/28/2012

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