Preparation of the Search Database

As mentioned in Section 3.1, a ligand-based virtual screening crucially depends on the knowledge of active query molecules, which can either stem from literature or in-house efforts. In some cases, a wealth of information is available, but not all known active compounds are equally suitable queries for virtual screening. The proper choice of the query and the preparation of both the query and the search database will be discussed in the following section. 

There is still a lack of studies regarding the impact of the affinity of the reference compounds on the success of virtual screening. Ligands vfith high affinity are a good choice to start with, but there is no evidence from literature that weaker queries (in the micromolar range) cannot lead to enrichments. 

However, if the target prefers lipophilic molecules over hydrophilic ones, even a perfect match of shape between query and hits does not lead to interesting biological activities if the compounds are not lipophilic enough or do not fulfill other crucial requirements of the active site. Only more insight into the properties of the binding site or the structure-activity relationships (SARs) of the ligands may help to decide how to proceed best in such cases. 

In this chapter, we discuss various methods that are applied for virtual screening. The simplest case is a similarity search where a single active query molecule and an 

Similarity searches can be performed on a small information basis that makes them suitable for the detection of actives in early project phases. The minimum information that is needed is a single active compound. In most cases, the aim is to detect new chemotypes, but of course similarity searches can also be used for the exploration of a hit class. The outcome can be controlled to a certain degree by the choice of the descriptors. 

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