Biomedical Engineering Reference
In-Depth Information
18
DOS-DERIVED SMALL-MOLECULE
PROBES IN CHEMICAL BIOLOGY
NICHOLAS HILL, LINGYAN DU, AND QIU WANG
18.1
INTRODUCTION
Small molecules are essential both as instruments of modern medicine and as probes
for studying biological processes [1]. By interacting with macromolecules, small
molecules can perturb polypeptide and nucleic acid function and modulate a wide
range of processes.
Traditionally, natural products have been a valuable source of structural diversity
and have enabled the development of compounds for both fundamental biological
studies and clinical applications [2]. However, successes have generally come about
on a case-by-case basis, and their use has been limited by a number of challenges
[1a,3]. In past decades, chemical genetics has emerged as a systematic approach
to exploring biological processes with small-molecule probes by identifying small
molecules that target a desired phenotype (forward chemical genetics) or the function
of a specific protein (reverse chemical genetics) [4].
Diversity-oriented synthesis (DOS), by design, aims to generate small-molecule
collections having a high degree of structural and functional diversity spanning large
regions of biologically relevant chemical space [5]. In many cases the chemical space
represented by a DOS library may include regions of known bioactivity (which, by
definition, are regions where biologically active agents have already been discovered)
and “untapped” regions of chemical space that may contain molecules with biolog-
ically relevant properties that have thus far escaped the attention of researchers and,
perhaps, even nature. Furthermore, a DOS strategy can facilitate the optimization of
