Biomedical Engineering Reference
In-Depth Information
targets and their small molecule regulators” [1]. For TOS compounds, knowledge of
the preselected targets can lead to some degree of rational design being implemented;
however, according to Schreiber, the second class of library should benefit from
high levels of structural diversity within the compound collection, so the deliberate
synthesis of such libraries can be considered to be DOS. An alternative definition was
offered later by our group, where it was suggested that “diversity-oriented synthesis
involves the deliberate, simultaneous and efficient synthesis of more than one target
compound in a diversity-driven approach to answer a complex problem” [2].
This statement leaves some room for interpretation; however, as the very nature of
diversity, in a chemical sense, is to some degree subjective, it provides a useful general
definition that can be applied across the majority of the examples of DOS that are
published today. The “complex problem” mentioned in this definition usually refers
to the discovery of novel biologically relevant compounds, and this is the context in
which DOS is usually discussed. However, as mentioned, this does not have to be the
case, as the DOS approach could potentially be applied to other problems, such as
the discovery of a novel ligand or catalyst for a reaction [2].
1.3 SMALL MOLECULES AND BIOLOGY
The term
small molecules
has no strict definition; however, it usually refers to poten-
tially orally bioavailable compounds that have a molecular weight of less than 1500 Da
[3] and that are distinct from naturally occurring biological macromolecules: DNA,
RNA, and proteins [4]. The label “small molecule” can therefore be applied across
the vast majority of synthetic drugs and naturally occurring secondary metabolites.
The ability of small molecules to interact with biological macromolecules, in
particular, proteins, and consequentially to exert specific effects, often in a selective
and dose-dependent manner, has led to them being regarded as powerful tools for
the study and manipulation of biological systems [5-7]. Indeed, the use of small
molecules in this way, to modulate biological function deliberately and selectively,
underpins the fields of medicinal chemistry (where molecules are used to treat disease
states) and chemical genetics (where molecules are used as probes to study biological
systems) [3,8,9].
The discovery of novel molecular entities or structural classes capable of these
specific interactions represents a significant challenge. In cases where the biological
target is well defined and understood, the rational design of ligands is sometimes
possible, especially when the structure of a native ligand or its single protein target
is known [6]. However, for other, less well understood disease states, or if a novel
mode of binding or biological target is sought, this is not possible. In these cases
high-throughput screening (HTS) of small-molecule libraries can provide an effective
solution [10]. Clearly, the composition of these libraries, in terms of the chemical
structures included within them, is an extremely important consideration [2]. As the
biological activity of a given molecule is intrinsically related to its chemical structure,
the greater the degree of structural variation between compounds within a library,
the higher the likelihood of achieving broad-ranging and distinct biological activity
across that library [11-13]. The presence of multiple structural classes within a
