Fragment screening methods

The main challenge for any fragment screening method is the detection of weak binders. The methods commonly used to detect fragments can be broadly broken down into biophysical and functional assays. 

In the past decade, an impressive repertoire of methods has been developed to permit drug development against soluble targets at the molecular level. In addition to fragment screening methods, structural biology has played a key role in this process. Although at present no... 

Mass spectrometry as a fragment screening method affords high throughput and low protein consumption. Historically, it was employed for detecting binders with covalent interactions with the protein of interest [49]. Recent advances in methodology and instrumentation have made it possible to use MS to detect... 

HPLC-screening method calculated-PCKOC fragment method, Muller Kordel 1996) 3.40-5.33 3.80-5.40 (range, calculated from sequential desorption of 11 urban soils lit. range, Krauss... 

HPLC-screening method calculated-PCKOC fragment method, Muller Kordel 1996)... 

Figure 1 Examples of fragment hit identification (showing fragment and target, bioassay activity and screening method).

There are various methods to conduct a fragment screening campaign. The most commonly utilized methods include various NMR techniques, mass spectrometry, SPR, and biochemical screens. X-ray crystallization is a preferred method since it provides a binding conformation, but can only be used when the target protein is well behaved. Various calorimetry techniques have also been used for fragment screening, but these have been less commonly utilized. The merits of each method have been discussed in the literature (26) and will not be outlined here. 

Over the past several years, descriptions of fragment collections have been published in journals as well as book chapters. In two recent reviews, a chapter from Evotec (33) compared several collections based their origins, while a journal article from Leiden University (26) summarized fragment collections based on the intended screening methods. We would like to present an overview by blending information from both reviews together to provide a more complete and updated picture (see Table 11.2 for details). 

In recent years there have been encouraging advances in screening technologies suitable for fragment screening. Even for an established method such as NMR, new techniques have been developed and put into practice at various companies that have expanded the scope of targets for FBDD. For example,... 

Overview of some key physical properties for selected fragment libraries and their associated screening methods... 

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