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Detection of protein-small molecule binding using a self-referencing external cavity laser biosensor.
Meng Zhang1, Jessie Peh, Paul J Hergenrother
1Department of Physics, ‡Department of Chemistry, §Department of Bioengineering, and ⊥Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
Journal of the American Chemical Society
|April 12, 2014
Summary
We developed a novel laser biosensor for label-free screening of small molecule drug interactions with protein targets. This high-throughput method accurately detects binding affinities, enabling efficient drug discovery.
Area of Science:
- Biochemistry
- Biophysics
- Analytical Chemistry
Background:
- High-throughput screening (HTS) typically uses colorimetric or fluorimetric assays for enzyme targets.
- Existing methods for nonenzymatic protein targets often lack simplicity or throughput.
- There is a need for label-free, high-throughput technologies for protein-small molecule interactions.
Purpose of the Study:
- To develop a novel, high-resolution, high-sensitivity biosensor for label-free detection of small molecule-protein interactions.
- To overcome limitations of existing HTS methods for nonenzymatic targets.
- To demonstrate the utility of the biosensor in drug discovery screening.
Main Methods:
- Utilized a self-referencing external cavity laser (ECL) biosensor.
- Achieved subpicometer wavelength accuracy to eliminate thermal noise.
- Immobilized various protein targets for interaction studies.
Main Results:
- Demonstrated detection of small molecule binding to immobilized proteins with affinities from subnanomolar to low micromolar.
- Successfully differentiated known inhibitors from inactive compounds in a carbonic anhydrase II inhibitor screen.
- Achieved high resolution and sensitivity in label-free detection.
Conclusions:
- The self-referencing ECL biosensor offers a powerful, label-free HTS platform for identifying small molecule modulators of protein targets.
- This technology addresses the limitations of current screening methods for nonenzymatic targets.
- The biosensor is effective for "needle-in-the-haystack" drug discovery screens.
