Virtual Fragment Scanning: Current Trends, Applications and Web-based Tools - Fragment-Based Drug Discovery - page 220

challenge for larger molecules [ 5 ] and scoring functions specific for fragments have yet to be
developed. However, software vendors are known to be actively pursuing suitable docking
and scoring functions explicitly for fragment screening. [ 6 ] Virtual screening of fragment
libraries has been most successful in applications where the active site is well character-
ized and degrees of freedom for molecular conformations and binding modes have been
substantially reduced.
An important ingredient to both empirical and virtual screening is the design of the frag-
ment libraries. Although this topic is covered in detail in other chapters, a short discussion
will be given in the context of virtual screening. Design criteria and comparison of the
physical properties distribution for various vendor offerings are presented in Section 9.2.

9.2 Fragment Databases

Due to the present popularity of fragment screening, vendors are now offering frag-
ment libraries for general screening. The prevailing hypothesis is that small fragments,
e.g. compounds of less than 300 Da, can be used to probe efficiently the functionality
and shape of a protein binding site. The chemical space spanned by all the combina-
tions of merging together small fragments in the library, i.e. de novo design of drug-like
molecules, can be much larger than can be achieved by corporate compound databases.
At present, ActiveSight, ChemBridge and Maybridge in particular offer fragment librar-
ies for screening, although they differ significantly in property distributions and sizes. [ 7 9 ]
Using the connection (SDF) files provided by the vendors, 384, 5213 and 848 molecules
were obtained for ActiveSight, ChemBridge and Maybridge fragment libraries, respect-
ively. In Figures 9.1-9.7, distributions for molecular weight, AlogP98, [ 10 ] polar surface
area (PSA) [ 11 ] , hydrogen bond acceptors (HBA), hydrogen bond donors (HBD), net charge

Molecular Weight Distributions

35

30

25

20

15

10

5

0

Molecular weight (Da)

Maybridge ChemBridge ActiveSight

Figure 9.1 Molecular weight distributions for ActiveSight, ChemBridge and Maybridge
fragment libraries.