With the cost involved in HTS, fragment screening (FBLD) has become over the last decade the method of choice to identify novel hit matter. Dan Erlanson from the Practical fragment blog and Ben Davis have just published a brief review (free of charge from Elsevier) looking at the potential experimental pitfalls. Nothing new there but clearly stating in one concise article what they call the ‘unknown known’ but more generally issues not only affecting FBLD.
The FBLD approach works but false positive hits are a common occurrence. These can be eliminated with a good understanding of the technique limitations and composition of your fragment file.
Do you know what’s in your fragment file: The authors look at the various issues leading to false positives from fragment stability, impurities and promiscuous frequent hitters.
The discussion in this review then goes in the limits of each of the popular biophysical screening techniques. From instrumentation artifacts to potential data misinterpretation leading to many false positives. ‘Knowing about possible problems can help you recognise them before investing additional resources or embarrassing yourself publicly’.