Developments in SPR Fragment Screening

ABSTRACT

Introduction: Fragment-based approaches have played an increasing role alongside high-throughput screening in drug discovery for 15 years. The label-free biosensor technology based on surface plasmon resonance (SPR) is now sensitive and informative enough to serve during primary screens and validation steps.

Areas covered: In this review, the authors discuss the role of SPR in fragment screening. After a brief description of the underlying principles of the technique and main device developments, they evaluate the advantages and adaptations of SPR for fragment-based drug discovery. SPR can also be applied to challenging targets such as membrane receptors and enzymes.

Expert opinion: The high-level of immobilization of the protein target and its stability are key points for a relevant screening that can be optimized using oriented immobilized proteins and regenerable sensors. Furthermore, to decrease the rate of false negatives, a selectivity test may be performed in parallel on the main target bearing the binding site mutated or blocked with a low-off-rate ligand. Fragment-based drug design, integrated in a rational workflow led by SPR, will thus have a predominant role for the next wave of drug discovery which could be greatly enhanced by new improvements in SPR devices.

KEYWORDS:

• Fragment-based drug design
• fragment screening
• molecular interaction
• surface plasmon resonance

Article highlights

• SPR devices are now state of the art for primary fragment screening.

• Main advantages include low product consumption, rapidity and high sensitivity.

• SPR is a selective and informative method that allows detection and removal of false positive binders.

• SPR is now validated for numerous challenging applications: GPCR, enzyme, and PPI.

• The critical points are the immobilization of a functional target and a limited use of the selectivity.

This box summarizes key points contained in the article

Financial and competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.