Pharmacotherapeutic targeting of G protein-coupled receptors (GPCRs) is perhaps the most important field of
drug design, as agents designed to control these receptors constitute more than half of the pharmacopeia. Initially GPCRs
were considered to be unitary entities, possessing all of their potential functionality in their characteristic heptahelical
core. Early models of the functional activity of GPCRs considered them to possess just a simple ‘on’ or ‘off’ status.
Recent research however has allowed us to realize that GPCR functionality is dependent upon many other proteins outside
of the heptahelical core, on the site of GPCR expression in a tissue or a microdomain in a cell, and, most importantly, on
the formation of differential ‘active’ states preferentially coupled to specific signal transduction structures. The
recognition of such signaling diversity has facilitated the ability to appreciate and identify ligands for GPCRs that
demonstrate a bias towards one signaling form of a receptor to another. However while potentially increasing our ability
for selective signal targeting, our approach to understanding the physiological ramifications of systemic signaling
manipulation is underdeveloped. This explosion in the complexity of GPCR signaling is now becoming familiar territory
to receptor biologists, yet the application of this knowledge to drug design is relatively limited. This review will attempt to
outline potential pitfalls and unseen benefits of using signaling bias in therapeutic design as well as highlighting new
applications such as Game Theory for uncovering new therapeutic applications for biased agonists.
Keywords: G protein-coupled receptor, biased agonist, signaling, drug design, aging, allostasis, E3 ubiquitin ligases, Src-family kinases, antagonists, signalsomes
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