Virtual screening process

The structure based virtual screening process includes also the use of some keywords. With these keywords FLAP fdters out matches and keeps them only if they make sense in terms of binding site shape. FLAP can also allow additional binding site volume (cavity expansion, useful when the protein structure under investigation is an homology model) and with the use of regions (definition of a sphere within each pharmacophore needs to have at least one point) or selection of a probe (enforcing a particular feature to be present in the calculated pharmacophores) certain constraints can also be added. 

Fig. 3.8. A workflow of in silico virtual screening process receptor-based and ligand-based approaches. (See black and white image.)...

Besides the use of pharmacophore fingerprints, 3D pharmacophore searches are among the most prominent 3D virtual screening techniques. Here distances between pharmacophoric features of the reference structures are compared with the respective distances in the structures of the search database. Again, these distances are conformation dependent and may be precomputed for a number of low-energy conformers in the search database to speed up the virtual screening process. This important approach is discussed in detail in a separate chapter of this book. 

If the virtual screening process is successful, the bioactive compounds will be enriched in the upper part of this ranked list. Enriched means that there are more active compounds in this part of the list than that one would expect based on the average content of bioactive compounds in the searched database. This enrichment can be determined only in retrospective studies where both the active and the inactive compounds in the database are known The emichment factor is typically used in such studies as a quality criterion for a particular virtual screening approach. Since the emichment factor depends on the chosen subset of the ranked list, it is common to calculate enrichment curves where the cumulated number of hits is plotted against the ranked list of compounds in the search database. In recent years, more and more researchers prefer other types of enrichment plots (e.g., ROC curves). The interested... 

Figure 11.4 Virtual screening process. Depending on the available ligand information, different methods and strategies can be applied during a typical virtual screen, often in parallel.

Figure 3 Scheinatic overview of the virtual screening process...

Note that this general flowchart is applicable to any stage in a project, from following up on an initial screening hit to fine-tuning the in vivo properties of a development candidate. The more information that is available, the more efficiently we can carry out a virtual screening process. We will describe how virtual screening is carried out today and point out ways to streamline this process. 

In this section we will begin to go through each step in the virtual screening process in some detail (Figure 4). 

Once docking has taken place we have an even more serious problem how to score the hits This is perhaps the most daunting problem in the entire virtual screening process. In principle, free energy methods such as FEP are the most accurate developed to However, such methods are... 

---