Biomedical Engineering Reference
In-Depth Information
are selected through a stepwise approach that first involves enumeration of a virtual
library and application of a series of physicochemical property filters to eliminate any
compounds that violate preset limits. The filters applied included molecular weight,
c
log
P
, rotatable bonds, and hydrogen-bond donors and acceptors. Once violators are
filtered out, the final library is selected to cover the greatest amount of chemical space
based on the maximal dissimilarity method, while retaining closely related analogs
for built-in structure-activity relationships upon screening in biological assays.
High-throughput screening of DOS libraries is often enriched in structure-activity
relationships (SAR) and/or SSAR to facilitate prioritization of hit clusters. Tractable
SAR is an important concept that can be used to validate different hit clusters as
well as to give confidence in developing hit compounds to lead compounds. Rather
than synthesis of additional analogs after the original HTS to achieve confidence,
upfront investment allows for this information to already be present in the screening
collection. This principle is illustrated with examples later in the chapter.
Once a hit cluster is identified, medicinal chemistry is most often required for
developing a lead candidate. Taking advantage of the initial DOS pathway allows
a chemist to systematically access most if not every atom in the compound. Such
an approach allows fundamental changes in the core skeleton rather than limiting
the development of SAR to appendage sites only. This principle can be illustrated
with a set of macrocycles recently published using a fragment-based domain shuf-
fling approach [18]. The synthetic route utilizes a glycal amino alcohol, a
-amino
acid, and an
o
-fluorobenzoic acid to give 16-membered lactams (Figure 17.3a). If
these compounds were found to be hits in an HTS campaign, one can easily imagine
how a modular approach could facilitate medicinal chemistry. In just one example,
the authors use a variety of amino acids to change substitution pattern, substitution
groups, and linker length yet continue to utilize the synthetic route developed orig-
inally (Figure 17.3b). The same approach could be applied to the benzoic acid or
amino alcohol motifs to probe additional SAR.
Despite the concept of DOS being relatively new, there is remarkable progress that
gives reason to continue efforts in this area. In the remainder of the chapter we focus
on examples of biologically active compounds derived from DOS pathways. When
possible, the principles described above will be presented. Case Study 1 focuses on
the identification of a small-molecule probe for the inhibition of
-cell apoptosis
from a DOS screening collection after a more traditional set of small molecules
failed. Case Study 2 looks at two campaigns focusing on antimalarial agents from
DOS pathways. Case Study 3 looks at the successes in targeting protein-protein
interactions and transcription factors using DOS compounds.
17.2 CASE STUDY 1: INHIBITION OF CYTOKINE-INDUCED
-CELL APOPTOSIS
Type 1 diabetes is primarily an autoimmune disease in which the insulin-secreting
-cells in the pancreas are destroyed by cytokine-induced apoptosis [19]. Hence
small molecules that can protect
-cells from cytokine-induced apoptosis can serve
