title: Fragment screening by surface plasmon resonance.
abstract: Fragment-based drug discovery is a validated approach for the discovery of drug candidates. However, the weak affinity of fragment compounds requires highly sensitive biophysical techniques, such as nuclear magnetic resonance (NMR) or X-ray crystallography, to identify hits. Thus the advantages of screening small fragment libraries are partly offset by the high cost of biophysical analyses. Here we present a method for biosensor-based fragment screening using surface plasmon resonance (SPR). In order to reduce the false positive detection rate we present a novel method of data analysis that incorporates multiple referencing with ligand efficiency. By implementing all necessary steps for assay design, data analysis and interpretation, SPR-based fragment screening has potential to eliminate all nonspecific (false positive) binders. Therefore, given the advantages of low protein consumption, rapid assay development and kinetic and thermodynamic validation of hits, SPR can be considered as a primary screening technology for fragment-based drug discovery.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, U.K.
authors.forename: Iva
authors.initials: I
authors.lastname: Navratilova
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, U.K.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Hopkins
keywords: Fragment screening; ligand efficiency; surface plasmon resonance