Virtual fragment screening

Huang N, Jacobson MP (2010) Binding-site assessment by virtual fragment screening. PloS One 5 el0109... 

Ruda GF, Campbell G, Alibu VP et al (2010) Virtual fragment screening for novel inhibitors of 6-phosphogluconate dehydrogenase. Bioorg Med Chem 18 5056-5062... 

Figure 2.23 Actives from PI3K (pi 10(3 isoform) virtual fragment screening (32 and 33).

Kawatkar, S., Wang, H., Czerminski, R., and Joseph-McCarthy D. (2009) Virtual fragment screening an exploration of various docking and scoring protocols for... 

This chapter describes the early hit discovery project to identify inhibitors of Hsp90 at Vemalis in 2002-2003. This generated the initial ideas from which series of preclinical candidate compounds were discovered, some of which continue in clinical trials for treatment of cancer [11, 17]. The very early work (virtual and fragment screening) was carried out within Vemalis before a collaboration was initiated with the group of Paul Workman at the Institute of Cancer Research. Subsequently, the project was partnered with Novartis, who were responsible for preclinical development and clinical trials while work at Vemalis continued on identification and optimisation of backup and follow-up compounds. 

A similar virtual fragment linking approach validated across a variety of different target classes has also been reported [88]. A combination of virtual and experimental (NMR, biochemical) screening methods was employed to identify novel scaffolds for the design of kinase-targeted libraries [89]. 

In addition, alternate virtual screening methods can incorporate activity-class-characteristic features. For example, by counting the number of activity-characteristic features in test compounds, active molecules were identified that possessed new combinations of activity-characteristic features that were not observed in reference compounds, resulting in chemotypes that were distinct from any of the reference compounds [13]. Similarly, virtual fragment linking [7] used features enriched... 

Cluster 1 Cluster 2 Cluster 3 Singleton 4 Singleton 8 Fragment screen Literature data Virtual screen etc... 

As the availability of crystal structures increased in the early 1990s, a number of experimental and computational methods were developed to use the structure of the protein target as a route to discover novel hit compounds. The methods include de novo design, virtual screening, and fragment-based discovery. These developments are covered in more detail in the later chapters of this book, but their main features can be summarized as follows. 

---