The
identification of sites on receptors topographically distinct
from the orthosteric sites, so-called allosteric sites, has heralded
novel approaches and modes of pharmacology for target modulation.
Over the past 20 years, our understanding of allosteric modulation
has grown significantly, and numerous advantages, as well as caveats
(e.g., flat structure–activity relationships, species differences,
“molecular switches”), have been identified. For multiple
receptors and proteins, numerous examples have been described where
unprecedented levels of selectivity are achieved along with improved
physiochemical properties. While not a panacea, these novel approaches
represent exciting opportunities for tool compound development to
probe the pharmacology and therapeutic potential of discrete molecular
targets, as well as new medicines. In this Perspective, in commemoration
of the 2013 Philip S. Portoghese Medicinal Chemistry Lectureship (Adventures in allosteric drug discoveryLindsleyC. W.LindsleyC. W.2013), several vignettes of drug discovery
campaigns targeting novel allosteric
mechanisms will be recounted, along with lessons learned and guidelines
that have emerged for successful lead optimization.