Allosteric Modulation of G Protein-Coupled Receptors: An Emerging Approach of Drug Discovery


Austin J Pharmacol Ther. 2013;1(1): 1011.

Allosteric Modulation of G Protein-Coupled Receptors: An Emerging Approach of Drug Discovery

Christopher Wild, Kathryn A. Cunningham and Jia Zhou*

Department of Pharmacology and Toxicology, Center for Addiction Research, University of Texas Medical Branch, USA

*Corresponding author: : Jia Zhou, Department of Pharmacology and Toxicology, Center for Addiction Research, University of Texas Medical Branch, Galveston, TX 77555; USA

Received: February 03, 2014; Accepted: February 10, 2014; Published: February 27, 2014


Allosteric modulation of G protein–coupled receptors (GPCRs) confers several significant advantages over the traditional targeting of orthosteric sites. While the field of allosteric modulation of GPCRs as we now know it will benefit from continued investigation, the explosion of interest has led to a more in–depth understanding as to precisely how allosteric modulators may usher in a new paradigm for drug discovery.

The widening gap between the cost of developing new medicines and successfully introducing therapeutics into the clinic cannot be ignored. The average R&D investment associated with bringing a drug development project to fruition is $1.2 billion over a 10–15 year time span [1]. While the annual amount spent on this endeavor has exploded since the 1950s [2], the number of approved drugs per billion U.S. dollars has decreased approximately 50–fold over the same time period [3]. Most certainly this trend cannot be attributed to a lack of technological advances considering the implementation of the high throughput capabilities in screening, sequencing and X–ray diffraction in addition to combinatorial and computational chemistry techniques available to the drug discovery team that collectively were once thought to usher in a new era in drug discovery. While the causes hampering productivity remain controversial [2–5], and the need for new targets is evident, a new paradigm with respect to how systems are targeted by small molecules is an intriguing idea that has recently gained momentum in the form of allosteric modulation. More precisely, the targeting of allosteric sites of GPCRs toward the generation of new therapeutics as a means to close the unsustainable gap between R&D costs and delivering relevant small molecules to the clinic is an exciting prospect.

The GPCRs are seven–transmembrane spanning receptors coupled to trimeric G proteins and, as a class, represent therapeutic targets for most approved medications marketed across the world yet only a small fraction of known GPCRs have been exploited for the treatment of diseases [6–8]. Traditionally, receptors of this type have been targeted with agonists or antagonists that bind to the orthosteric site that usually accommodates the endogenous ligand(s) for a given receptor. Targeting in this way can become problematic especially when the receptor belongs to a family of subtypes that share high sequence homology at the orthosteric site, usually a requisite to bind the endogenous ligand across the family of receptors. Notable examples include the metabotropic glutamate receptors (mGluRs) and serotonin receptors (5–HTRs) which are comprised of 8 and 14 receptor subtypes respectively, underscoring the importance for subtype selectivity [9,10]. This major limitation can potentially be overcome through the targeting of allosteric sites that are topologically distinct from the orthosteric sites. Conventional wisdom suggests that allosteric sites are less conserved across related receptors due to decreased evolutionary pressure that would otherwise be requisite to maintain an orthosteric binding pocket capable of accommodating the endogenous ligand(s) [11]. In short, allosteric modulation provides an opportunity to specifically target receptors that belong to a subfamily of similar GPCRs, thereby minimizing off–target effects, a significant advantage over typical agonism⁄antagonism acting at the endogenous ligand binding pocket. Moreover, most GPCR therapies are based on chronic exposure of the receptor to orthosteric ligands which raises the important issue of understanding and investigating the longterm regulatory processes of the receptors and the implications as related to decreased clinical efficacy due to desensitization and up⁄ down regulation of the target receptor. Allosteric modulators that lack intrinsic activity and only modulate the action of the orthosteric ligand may overcome the aforementioned issues, another major advantage over traditional approaches to receptor targeting. Another potential benefit of allosteric modulators is based upon the possibilitythat structural modifications can be designed to result in separate control of affinity and efficacy leading to the fine–tuning of GPCR activity in a manner that depends on the presence of the endogenous ligand [12].

The small molecule allosteric modulation of GPCRs can promote a conformational change in the receptor that often alone produces no noticeable downstream effects, but in the presence of an orthosteric ligand there can be several possible outcomes [Figure 1]: (i) positive allosteric modulators (PAMs) increase the binding affinity and⁄ or efficacy of orthosteric ligands, (ii) negative allosteric modulators (NAMs) are the antithesis of PAMs, decreasing binding affinity and⁄ or efficacy of the orthosteric ligand, (iii) silent allosteric modulators (SAMs) bind to the allosteric site without actuating a change in orthosteric binding or efficacy. The fact that allosteric modulators can lack intrinsic activity in the absence of the orthosteric ligand confers two important benefits: (i) preservation of temporal and spatial endogenous tone while fine–tuning the desired biological signaling outcome, and (ii) a ceiling effect that can minimize side effects [11]. Some allosteric modulators such as ago–PAMs can have intrinsic activity which may provide an opportunity to activate or diminish GPCR–mediated signaling in the absence of ligands that act at the orthosteric site of action. The leveraging of biased signaling (promotion of one signaling pathway at the expense of another at the same receptor) and probe dependence (differing signaling outcomes based on the identity of the chosen orthosteric ligand at a given receptor) may be exploited as novel modalities toward the treatment of disease. Yet another advantage is that so–called “undruggable” GPCRs that areactuated by intractable stimuli (i.e., large peptides) can be modulated allosterically by synthetically accessible small molecules, opening a new avenue toward targets previously unassailable [13].