Advances in G Protein-Coupled Receptors Biophysical and Medicinal Chemistry

Dear Colleagues,

The largest family of human cell surface proteins, which is known as guanine nucleotide-binding protein coupled receptors (GPCRs), play important roles in biological processes such as vision, sensing and neurotransmission. In adrenergic receptors, a subfamily of GPCRs that can be found in many cells, the binding of a catecholamine, especially norepinephrine (noradrenaline) and epinephrine (adrenaline), can stimulate the sympathetic nervous system, effect blood pressure, myocardial contractile rate and force, airway reactivity and a variety of metabolic and central nervous system functions. Moreover, GPCRs have also been found to be actively involved in cancer growth and development. Numerous extracellular molecules, including hormones and drugs, can activate and inactivate GPCRs acting as agonists and antagonists, respectively, the former usually leading to conformational changes associated with specific protein functions. Agonists and antagonists interacting with adrenergic receptors have been successfully employed in the treatment of various diseases, such as hypertension, angina pectoris, congestive heart failure, asthma, depression, benign prostatic hypertrophy and glaucoma. Given their implication in different human diseases, GPCRs have become the target of about 35% of all marketed pharmaceutical drugs in the US and worldwide.

During the last two decades, thanks to technological advances in crystallization methods, the X-ray crystal structures of GPCRs have been released in an exponential manner. In 2012, Robert Lefkowitz and Brian Kobilka were awarded the Nobel Prize in Chemistry for their groundbreaking discoveries revealing the structure and function of GPCRs at a molecular level. More than 150 GPCR structures published in the Protein Data Bank are co-crystallized with ligands. Contemporaneously, an increasing number of homology models has also contributed to covering more than 10% of the GPCR superfamily. Over the last ten years, experimental and computational studies have proven that adrenergic receptors act as amplifiers of signals from the extracellular environment to intracellular proteins, even when activated by agonists, with a conformational heterogeneity in which inactive, intermediate and active states coexist. Furthermore, GPCRs have also started to be seen as allosteric machines, which can be activated not only by agonists but also by ions, lipids, cholesterol and water.

Since understanding receptor–drug interactions at an atomic level is essential in structure-based drug discovery (SBDD), molecular docking and molecular dynamics (MD) simulations have become widely employed tools to aid drug design by revealing binding affinity, reaction mechanism and protein–ligand interactions. This Special Issue aims at gathering original contributions describing the biophysical properties and the interaction of GPCRs with biologically relevant molecules and drugs. Research articles using both computational and experimental approaches are particularly welcome.

Dr. Andrea Catte
Guest Editor

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• GPCRs
• ligand-receptor interactions
• allosteric modulation
• structure-based drug design
• computer-aided drug design
• molecular docking
• molecular dynamics simulations