✍ Scribed by Jahnke, Wolfgang; Erlanson, Daniel A.
No coin nor oath required. For personal study only.
drug discovery" [6-8, 11, 12] has a number of other advantages over conventional screening, including a more efficient sampling of chemical space and a higher hitrate due to lower molecular complexity [13]. Both of these factors mean that the number of compounds screened can be considerably reduced.
A key challenge in fragment based drug discovery is the detection of hits, because weakly binding fragments are difficult to detect reliably using "conventional" bioassay-based screening methods. However, a variety of biophysical methods such as X-ray crystallography [12,14] (chapter 11), protein NMR [8, 15] (chapters 8 and9), surface plasmon resonance [16], and mass spectrometry [17] (chapter 13) have been successfully used to detect the binding of fragments to a variety of protein targets. The use of crystallography as a screening technique has the additional advantage of very high sensitivity (capable of detecting binding in the millimolar range, and therefore allowing the screening of even smaller fragments) as well as providing precise structural details of the interaction between hit and target. Thus, this technique not only provides an efficient means to detect weak binders, but also allows for the most rapid and efficient hit optimization by structure-based design techniques. In addition, crystallography is less likely to suffer from the problem of false positives, which are intrinsic to most other screening techniques.
In this review, we describe how X-ray crystallography forms the central part of our fragment-based screening platform, which we term Pyramid [18]. We present a discussion of the issues involved in using crystallography as a screening technique, the technology developed to address these, and selected case studies. We also discuss the evolution of the Pyramid approach in which high-throughput crystallography is coupled with other biophysical techniques, such as NMR, resulting in an integrated fragment-based discovery platform.
📜 SIMILAR VOLUMES