Fragment screening by surface plasmon resonance.

Area of Science:

• Biochemistry
• Drug Discovery
• Biophysics

Background:

• Fragment-based drug discovery (FBDD) is effective but relies on costly biophysical techniques like NMR and X-ray crystallography.
• The high cost and complexity of traditional methods limit the advantages of screening small fragment libraries.
• Weak fragment compound affinity necessitates highly sensitive detection methods, posing a challenge for efficient screening.

Purpose of the Study:

• To present a novel biosensor-based fragment screening method using Surface Plasmon Resonance (SPR).
• To introduce a new data analysis approach incorporating multiple referencing and ligand efficiency to reduce false positives.
• To establish SPR as a primary screening technology for FBDD by addressing limitations of current methods.

Main Methods:

• Development and implementation of an SPR-based biosensor assay for fragment screening.
• Application of a novel data analysis method combining multiple referencing and ligand efficiency.
• Validation of assay design, data analysis, and interpretation for SPR-based fragment screening.

Main Results:

• The SPR method demonstrates potential for eliminating nonspecific (false positive) binders.
• The novel data analysis significantly reduces the false positive detection rate in fragment screening.
• SPR screening offers advantages including low protein consumption and rapid assay development.

Conclusions:

• SPR-based fragment screening is a viable and cost-effective alternative to traditional biophysical techniques.
• The developed method provides kinetic and thermodynamic validation of hits, enhancing drug discovery pipelines.
• SPR can be considered a primary screening technology for fragment-based drug discovery due to its efficiency and accuracy.