Biomedical Engineering Reference
In-Depth Information
FIGURE 10.4
Box plots of the molecular complexity measures of 6152 commercial com-
pounds (CCs), 5963 diverse compounds from the academic synthetic chemistry community
(DC
), and 2477 natural products (NP). The boxes enclose data points with values within the
first (Q1) and third (Q3) quartiles (i.e., enclose 50% of the data); the arrowheads pointing to
the right and left denote the median and mean distributions, respectively; the gray band inside
the box indicates the 95% confidence interval of the mean value; the lines above and below
indicate the upper and lower nonoutlier values [calculated as Q3
Q3) and
Q1 - 1.5
×
(Q1
−
Q3), respectively]. The squares indicate outliers. Selected statistics of each
distribution are summarized in the table. (a) Measure of stereochemical complexity calculated
as the portion of carbon atoms that are stereogenic. (b) Measure of shape complexity calculated
as the ratio of sp
3
-hydridized carbon atoms to total sp
3
- and sp
2
-hybridized carbons. The data
sets were obtained from the work reported by Clemons et al. [85].
+
1.5
×
(Q1
−
415,284 compounds published in the
Journal of Medicinal Chemistry
between 1959
and 2009 showing that since the mid-1970s, molecules published in this journal have
consistently had less sp
3
character than that of marketed drugs [61].
The molecular complexity, physicochemical, and structural diversity profile of a
large collection of 30 small-molecule combinatorial libraries was also surveyed using
a complementary set of chemoinformatic approaches [55]. In the same study, the com-
plexity and profile of physicochemical properties of the natural products database
TCM was also analyzed. It was concluded that the high molecular complexity and
structural uniqueness of the combinatorial libraries and natural product collections are
indicative that these databases are suitable for interrogating novel regions of the chem-
ical space. Results of this and other studies also supported the rationale to develop
more complex, natural product-like libraries for improved drug discovery [91].
It should be emphasized that increasing molecular complexity is not the only
criterion to consider when screening existing collections or designing new libraries;
other properties have to be balanced. For example, a recent analysis reviewed by Leach
and Hann [88] suggests that off-target promiscuity increases with molecular weight
and, in particular, with lipophilicity. Since the evidence that supports the fact that
molecular complexity is associated with improved drug discovery is growing, it has
