Biomedical Engineering Reference
In-Depth Information
FIGURE 10.2
(
Continued
)
property diversity of the LOLs over individual libraries. That work represented the
first comprehensive quantification of the diversity of LOLs, providing a solid approach
to comparing and contrasting the diversity of DOS libraries with existing drugs or
any other compound collection [48]. LOLs have also been analyzed using molecular
fingerprints (see below) [70].
As part of an ongoing effort to identify novel inhibitors of natural origin for the
emerging epigenetic target DNAmethyltransferase (DNMT) [71], the chemical space
of two natural product collections, including compounds from the TCM database,
were compared to the property space of approved drugs, synthetic commercial com-
pounds, and a focused library directed to identify DNMT. It was concluded that the
DNMT-focused library and the two natural products collections have molecules with
properties similar to those of approved drugs [72].
In a separate study, the chemical space of more than 28,000 compounds from the
TCM database was compared to a large collection of small-molecule combinatorial
libraries with 30 different scaffolds (Figure 10.2b) and a database of a commercial
vendor library. The small-molecule libraries are part of the
scaffold ranking plate
that
has been designed over the years to introduce diversity in structures and chemical
properties. Experimental evidence has shown that this plate is a valuable tool in the
rapid selection of the most promising scaffolds for further screening and identifying
novel lead compounds [1,19,23]. Six medicinally relevant properties were used to
define the chemical space: MW, RB, HBA, HBD, TPSA, and
S
log
P
(see above).
That study revealed that, in general, compared to the other collections considered in
that work, TCM has the largest values of HBD, HBA,
S
log
P
, and TPSA. Concerning
the size as measured by MW, TCM had the largest molecules overall. It was also
concluded that a large proportion of the compounds in the combinatorial libraries
have different degrees of overlap with the property space of currently approved drugs
[55]. Of note, studies comparing drugs launched prior to 1983 (“old” drugs) and drugs
launched between 1983 and 2002 (“new” drugs) reveal that the mean and median RB
and MW values are larger in new drugs [62,63].
