[Fragment screening using surface plasmon resonance optical biosensor technology].

Area of Science:

• Biophysics
• Biochemistry
• Analytical Chemistry

Context:

• Surface Plasmon Resonance (SPR) is an optical biosensor technology used for label-free, real-time detection of molecular interactions.
• Fragment-based drug discovery (FBDD) is a crucial early-stage process in developing new therapeutics.
• SPR offers advantages in FBDD, including low protein consumption and detection of low-affinity binders (K(d) in mM range).

Purpose:

• To highlight the utility and advancements of SPR biosensors in fragment screening for drug discovery.
• To address the challenges of detecting weak fragment binding and mitigating false positives in SPR assays.
• To provide guidance on developing robust SPR assays and evaluating hit candidates.

Summary:

• SPR biosensors are effective for fragment screening, a key step in drug discovery, due to their label-free, real-time detection capabilities and low sample requirements.
• While historically challenging, advancements in SPR technology and experimental protocols now allow for the detection of low-affinity fragment binding.
• Medium-throughput SPR instruments facilitate rapid screening of large compound libraries, with careful assay design needed to manage false positives from non-specific binding.

Impact:

• SPR technology enables efficient screening of compound libraries, accelerating the identification of potential drug candidates.
• Well-designed SPR assays with high reproducibility (Z'-factor > 0.6) are essential for reliable hit identification.
• Detailed analysis of sensorgrams, binding stoichiometry, and dose-dependence is critical for validating true hits and guiding structural studies (e.g., X-ray crystallography).