Biophysical screening

Fig. 19.11 Scheme for a structure-based biophysical screening for lead finding. 

As long as the virtual structure-based screening procedure identifies compound proposals that can be realized and tested in a short period of time, the accuracy lacking in the scoring functions can be compensated and finally validated by the biophysical screening experiment itself. 

Trosset J-Y, Dalvit C, Knapp S et al (2006) Inhibition of protein-protein interactions the discovery of druglike beta-catenin inhibitors by combining virtual and biophysical screening. Proteins 64 60-67... 

In this overview of fragment-based drug design, we will expand on the application of NMR and X-ray crystallography as the tools for biophysical screening. Common protocols will be presented, as well as the strengths and limitations of each approach. 

The decision on what type of screen to use in FBDD is affected by many different factors availability of protein for screening, compound selection, throughput, turnaround and rate of false positives and negatives. The resolution of these questions from target assessment directly impact the possibilities in this section. If there is not sufficient protein for a biophysical screen, a biochemical screen is the only choice. Protein that is not stable for... 

The primary choice in this assessment is whether to utilize a biochemical or biophysical screen as the primary filter. Although it seems like an either/or choice, this is a false dichotomy. The most successful fragment screens obtain orthogonal data, i.e. both biochemical and biophysical data in parallel or in quick succession. With orthogonal data, the probability of false positives (or negatives) is reduced. Most commonly biochemical and biophysical data are obtained. However, all the different biochemical and biophysical screens can be considered orthogonal. We would recommend that if two biophysical methods are to be used at least one should be a direct method (discussed below). As is noted many times in this book, rapid iterations among the various data sources are the key to a successful process. 

Hennig M, Ruf A, Huber W (2011) Combining biophysical screening and X-ray crystallography for fragment-based drug discovery. Top Curr Chem. doi 10.1007/128 2011 225... 

Combining Biophysical Screening and X-Ray Crystallography for Fragment-Based Drug Discovery... 

Keywords Biophysical screening Fragment-based drug discovery Inhibitor Protein-protein interactions Structural biology... 

A. Ciulli, Biophysical Screening for the Discovery of Small-Molecule Ligands, in Protein-Ligand Interactions Methods and Applications, ed. 

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