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Confident compound selection with Biacore™ 4000

Bringing new drugs to market remains a tremendous challenge, despite huge investment and numerous technological developments. Biophysical methods that provide high quality binding and selectivity data are gaining importance, particularly in structure-based drug discovery.

Biacore 4000 is designed for large-scale studies of LMW compound interactions with target proteins. It provides the sensitivity, information-rich high quality data and throughput required for a wide range of drug discovery applications, from primary screening of fragment libraries, through hit validation and lead optimization.

 • High quality, real-time data based on therapeutically relevant  binding properties (selectivity, affinity, kinetics)
 • Hardware and software designed to provide the throughput required for large-scale analysis
 • Low consumption of  target proteins
 • Label-free, direct binding assays facilitate analysis of problem targets with unknown or unstable substrates
 • Low baseline noise for resolution of low responses
 • Resolution of fast off-rates with 10 Hz data collection rate

As described below, GE Healthcare also provides an add-on software package with dedicated tools to enable customers to fully exploit the capabilities of the system for LMW drug discovery applications.

Biacore 4000 LMW Extension Package

 A powerful solution for fragment screening, lead selection & optimization
This software package enables efficient and confident decision making in small molecule drug discovery applications. Dedicated software tools for screening of fragments and other LMW compounds speed up assay setup and streamline evaluation. Additional kinetic fitting models and enhanced data export functionality support a range of assays from screening to characterization applications, such as in lead optimization.

 

• Rapidly clean fragment libraries and confidently identify
optimal binders for further analysis using dedicated tools
for assay setup and data evaluation
• Conveniently  export data to analysis software such as
Spotfire™ or Excel™  for  customized evaluation and
simplified workflow integration
• Address a broader range of compound-target interactions
using additional kinetic fitting models

The main  technical features and associated application benefits  provided by the software package are described in more detail below.

Speed up and simplify compound screening & characterization

• Go directly to: Fragment screening>>

• Go directly to: Kinetic models>>

• Go directly to: Data export>>

• Go directly to: Literature download>>

 
Dedicated tools for screening of fragments & other LMW compounds
LMW fragments commonly exhibit low affinities, leading to solubility issues at the high concentrations required for screening assays. To address these challenges, Biacore 4000 LMW Extension Package provides dedicated tools to facilitate library clean-up, single concentration screens for selection of binders, and affinity analysis of binders. Predefined methods for assay setup and evaluation are supplied, which can also be modified as required, providing flexibility in assay design.

Clean Screen for efficient library clean-up
This tool provides rapid identification and elimination of undesirable sticky compounds that show persistent binding to the surface and which may disturb subsequent analysis cycles.

• Samples are run over target(s) and a blank surface control
   - Assay setup using predefined run method
• Evaluation function automatically displays samples according to three
   classifications
   - General residual binders (to all spots)
   - Selective residual binders (to some but not all spots)
   - Non-residual binders
• Undesirable samples can then be exluded from further analysis

Display of results in Clean Screen
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Binding Level Screen for rapid prioritization of binders
Providing a rapid overview of the library content this tool identifes samples with binding levels above a defined cut-off point, and enabling their efficient prioritization for further analysis. One concentration of each fragment is run over target(s) and a reference surface. If multiple targets are immobilized in each flow cell, selectivity information can be obtained from a single sample injection. Evaluation focuses on identifying fragments with undesirable binding behavior such as secondary interactions and atypical binding curves. 

• Binding levels are plotted against cycle number
• Samples with levels above a cut-of boundary are identified
   - Included in subsequent assays
• Binding behavior indicators automatically identify and classify
   each fragment
   - Samples with atypical behavior can be excluded from
     subsequent assays

Display of results in Binding Level Screen
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Affinity Screen for reliable affnity ranking
Affinity Screen provides tools for verification of binding and affinity ranking of fragments. The analysis uses a concentration series of fragments run over targets and reference. Predefined methods support assay setup and data evaluation. To circumvent fragment-associated challenges, such as solubility issues and difficulties in reaching the binding levels needed for classical affinity determination, novel assay setup guidelines and data evaluation tools are provided.

•  Predetermined Rmax (theoretical maximum binding level) estimated
   using a control compound
• Evaluation based on data measured early during the binding phase
   - Minimizes disturbances from secondary interactions
• Automatic data validation support is provided, prompting inspection of
   data that does not fulfil quality parameters
• Affinity is estimated using a one-site model, but software automatically
   suggests data that might benefit from a multi-site model  

Data validation in Affnity Screen
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Single & multi-site model options
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Extended export functionality for flexible data analysis
Supporting a broad range of screening and characterization applications in drug discovery, detailed information can easily be exported to visualization software such as Spotfire and Excel. Data that can be exported includes run and sample information, curve markers, ranking information, cut-off values, affinity and kinetic constants, and baseline adjusted sensorgram data.

• Allows customized data comparisons and visualizations
• Enables combination and compilation with data from orthogonal studies for more confident decision making
• Simplifies overview of multiple projects

Additional kinetic fitting models
Biacore 4000 LMW Extension Package provides additional kinetic fitting models for broader applicability. This facilitates applications from screening through to lead optimization across a wider range of compound-target interactions. The models included are:

• 1:1 dissociation: fits the dissociation phase when the analyte binds to one interaction partner attached to the surface
• Heterogeneous ligand: when the analyte binds independently to heterogeneous interaction partners or binding sites on the surface
• Bivalent analyte: used for analytes with two binding sites

Download Product & Application Literature

To download the pdf's below, please enter your login details. If you do not have a Biacore website account yet, you can sign up here.

Biacore 4000 LMW Extension Package Data File (1 MB)
Application Note:

Application Note: Fragment library screening and characterization with BiacoreTM 4000

(1 MB)