Chemistry Reference
In-Depth Information
the complete molecule. There are many variations to this method; most methods differ in
the precise definition of building blocks.
O
O
NH
H
(a)
O
OH
H
2
N
O
O
O
O
O
BC
NH
BC
BC
N
(b)
(c)
O
BC
BC
OH
H
2
N
O
O
O
BC
O
(d)
(e)
BC
BC
N
BC
Figure 8.6
Molecular building blocks, according to Bemis and Murcko.
[28]
(a) The structure
that will be fragmented (CID9959891, see Figure 8.1). By removing (b) the side-chains from
this structure, (c) the molecular framework is revealed. The framework consists of one or more
(d) ring systems connected by (e) linkers. The connection point to the framework or rings is
indicated by a rectangular label composed of the letter B and the atom type that it is connected
to. For instance, the BC label means a carbon connection point in the framework.
Virtual retro-synthesis.
Another way to split a molecule into smaller parts is by virtual
retro-synthesis. This method applies a set of breaking rules based on chemical reactions.
Bonds that are typically formed by one of these reactions, are cleaved, essentially reversing
synthesis. The resulting fragments are precursors from which the molecule can be synthes-
ized using the set of chemical reactions. Although this approach might seem useful from
a chemical point of view, it is not so appropriate for precise analysis. A different choice
of synthesis rules may result in a different set of fragments. In addition, rules may conflict
or the derived fragments may overlap. Moreover, there are indications that actual syn-
thesis may not be reflected very well (as indicated e.g. by Vinkers
et al
.
[
24
]
). For a general
overview of retro-synthesis, the reader is referred to a review by Todd.
[
25
]
Furthermore, a
recent application of this synthetic approach was described by Vieth and Siegel.
[
26
]
They
investigated four sets of bioactive molecules, fragmented these and analyzed the fragment
distribution within a single set and between the four sets. An interesting example is the
distribution of the -lactam framework within antibiotics. This framework was prevalent
