Drug Discovery Opportunities through Allosteric Modulators of G Protein-Coupled Receptors

This article is about the new opportunities for drugs to be discovered through the identification of allosteric ligands. These have generally not been the main focus of GPCR, or G-Protein Couple Receptors. GPCR are located in cell membrane surfaces and respond to a variety of extracellular signaling. They have been investigated for the discovery of several drugs that moderate specific GPCRs. When GPCRs are stimulated by the proper ligand, intracellular signal transduction is initiated. Activation of  β-arrestin pathways and activation of G-proteins are the two mechanisms of signal transduction. The binding of the lingand stabilizes the receptor, allowing it's C-terminal domain to interact with protein complex and its Gα portion to hydrolyse GTP and interact with adenylate cyclase and/or phospholipase C. The receptor is phosphorylated when it reacts with G-protein-coupled receptor kinases and is able to bind β-arrestins. This prevents more G-protein signaling from occurring and also begins a series of intracellular events that are independent from G-proteins.

GPCRs have been pharmacological targets. However, only certain classes of GPCRs are able to be targeted with drugs. The article is proposing that idenitfying allosteric ligands that bind to different sites other than the orthosteric site will provide new opportunities for drugs to be produced. Allosteric modulators allow for enhanced saturability as well as selectivity. Because they cause conformational changes in their receptors, allosteric modulators can alter affinity and capability. Therfore, allosteric modulators can impact how receptors relate and respond to their binding partners, producing selective responses. The article then describes different techniques that can be used to identify allosteric modulators.

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