Allosteric Modulators of GPCRs

Dear Colleagues,

G protein-coupled receptors (GPCRs) are the largest group of receptor proteins that are targeted by more than 30% of drugs. As a result, the problem of selective regulation and modulation of GPCR activity is a mainstream in molecular biology and biochemistry. Along with the high-affinity orthosteric binding site, GPCRs contain allosteric binding sites that are localized both in the transmembrane domain and in the extracellular and cytoplasmic loops of receptors. These sites are targets for compounds with activity of positive (PAM), negative (NAM) and silent (SAM) allosteric modulators, as well as for compounds with activity of full and inverse allosteric agonists of GPCRs.

At present, a large number of endogenous allosteric GPCR regulators have been discovered and studied, including metal cations, lipids and their derivatives, steroid hormones, amino acids, peptides, and proteins. The most important role in the etiology and pathogenesis of autoimmune diseases belongs to specific antibodies with the activity of allosteric regulators and modulators of GPCR. In recent years, an intensive development of allosteric regulators has been carried out, which have a number of advantages over orthosteric ligands and are capable of modifying their activity. PAMs potentiate the effects of full orthosteric agonists, reducing their effective doses and thereby preventing side effects. NAMs prevent hyperactivation of GPCR but at the same time do not block its activity. Allosteric regulators are highly specific for intracellular cascades and have more diverse mechanisms of their regulation, including due to the modification of the effects of orthosteric ligands.

This Special Issue of the International Journal of Molecular Sciences is devoted to the prospects and unresolved problems of allosteric regulation of GPCR, and the main topics will be: (1) search, design, and development of different classes of allosteric GPCR regulators, including endogenous allosteric modulators, (2) deciphering the targets and molecular mechanisms of action of the endogenous and artificial allosteric GPCR regulators, (3) study of the structure and organization of allosteric GPCR sites and their role in the functioning of GPCR, (4) the effect of oligomerization of GPCR and their complex with the receptor-activity-modifying protein (RAMP) on allosteric effects; (5) allosteric GPCR regulators and control of biochemical and physiological processes, (6) impaired allosteric regulation of GPCR and pathogenesis of autoimmune, neurodegenerative, and other diseases.

Authors are invited to submit original and review articles on the allosteric regulators of G protein-coupled receptors to be published in this Special Issue of the International Journal of Molecular Sciences.

Prof. Alexander Shpakov
Guest Editor
Dr. Kira V. Derkach
Co-Guest Editor

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