Biomedical Engineering Reference
In-Depth Information
of the bacterial genome. Sixty-seven campaigns were run against specific targets, of
which only 15 resulted in hits, and five of those resulted in leads. Three additional
phenotypic cell-based assays were also run, but no viable leads were identified. Such
poor screening results lead to at least two possible conclusions being formed. The
first is that the biological targets screened are not ideal for modulation by a small
molecule and are therefore undruggable. The second is that compounds traditionally
used in HTS campaigns are poorly suited for the discovery of novel leads against
these new types of biological targets. It is often a combination of both parameters,
although scientists at GSK point to the lack of chemical diversity and compounds
containing desirable chemical properties within their screening collection.
One result to come from the recent failures in drug discovery has been next-
generation synthesis, a shift away from traditional small-molecule collections in an
attempt to access novel chemical space. Several approaches have been introduced
over the past decade in an attempt to define an optimal screening collection in which
more tractable hits are identified for medicinal chemistry efforts. These include
fragment-based drug discovery (FBDD) [4], diversity-oriented synthesis (DOS) [5],
biology-oriented synthesis (BIOS) [6], function-oriented synthesis (FOS) [7], natural
product-derived/target-oriented synthesis, and recently, lead-oriented synthesis [8].
Fragment-based drug discovery has served as a useful approach in the discovery of
a variety of difficult targets, including protein-protein interactions. FBDD focuses
on screening a small number of low-molecular-weight compounds against a known
target using biophysical methods. Most often, FBDD hits are weak binders but have
high ligand efficiencies. Progression of the hit compound to a lead with a strong
binding affinity usually requires a crystal structure of the protein with the ligand.
Biology-oriented synthesis utilizes the underlying framework of natural products for
the synthesis of compound collections. Lead-oriented synthesis incorporates more
drug-like properties into the screening collection so that compounds identified from
a primary high-throughput screen can easily be advanced to in vivo proof-of-concept
studies. Diversity-oriented synthesis strategies provide new types of small molecules
that are currently lacking in most screening collections, so that chances of finding hits
against new types of biological targets can be enhanced. Chemical complexity in the
final product and the modular assembly of the core scaffolds are both hallmarks of
DOS. Although these approaches are defined, hybrids of two or more of the concepts
have been published. In the case of DOS, it has been utilized in FBDD [9] and used
in a logical design that incorporates drug-like properties, similar to “lead-oriented
synthesis” [10].
DOS allows access to novel chemical space and structural complexity. Although
DOS is defined by the approach and not the compounds it produces, it is associated pri-
marily with complex compounds that have been inspired by natural products. Screen-
ing collections have generally been dominated by flat, achiral compounds available
from commercial sources, with complexity being introduced through screening small
numbers of natural products (examples are shown in Figure 17.1). Increasing the con-
tent of structurally complex compounds to include DOS compounds provides novel
chemical space compared to that of traditional small-molecule collections similar
to GSK's, which failed in their antibacterial campaign. Complexity should not be
