A combinatorial set of molecules is formally
generated by combinatorially placing substituents at selected
positions of a core structure (invariant part). Combinatorial
representations of molecule sets are common in the
chemical patent literature,
combinatorial chemistry and in context with
QSAR studies.
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Here we are choosing the Markush structure example of
Barnard and Dawns that
also was selected by Maclean and Martin [1] to discuss combinatorial
library representations. This example demonstrates four forms of
variation in generic structures:
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Substituent variation:
R1 =
methyl or ethyl group;
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Homology variation:
R2 =
alkyl group;
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Position variation:
R3 =
amino group;
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Frequency variation:
m =
1, 2, or 3.
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The following is a corresponding CurlySMILES notation:
Oc1c {+Rcc=C{-},CC{-}} c {+R} c( C{-}{+nn=1-3} Cl)cc1 {+Yc=N{-};p=6}
The core structure is phenol, represented by the SMILES code
in black. The four variations are represented as
OPAM
annotations. The substituent
variation in ortho
position to the hydroxy group is included via annotation
marker +R indicating alkyl group
substitution. The two substituents C{-}
(methyl) and CC{-} (ethyl) are
given as a comma-separated pair via key
cc .
The homology variation in meta
position to the hydroxy group is included by solely using
annotation marker +R , representing
a potentially unlimited class of alkyl groups.
The position variation of the
amino group at the other ortho and para positions
is encoded as +Y
(for “any group”) annotation, which is anchored
at atom position 7 of the SMILES notation (ortho position).
The second position possibility for the amino group is
atom position 6, specified via key
p .
The frequency variation, which defines a
range for the occurrence of a structural repeat unit (SRU), is
encoded by using the CurlySMILES format for an SRU
(in this case a methylene group).
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A typical combinatorial library
is formally generated by substituent and/or position variation.
Frequency variations are less likely to occur in
synthesized libraries. But any type of variation can be useful
to define a virtual library. The given example demonstates that
CurlySMILES supports efficient serialization of diverse
structurally defined libraries for network transport, querying
and the study of interlibrary relationships.
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