Impact of Recently Determined Crystallographic Structures of GPCRs on Drug Discovery

Deflorian, Francesca; Mason, Jonathan S.; Bortolato, Andrea; Tehan, Benjamin G.

doi:10.1002/9781118681121.ch19

Cited by 2 publications

(1 citation statement)

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“…Allosteric modulation is an elusive phenomenon, details of which are difficult to elu cidate with in vitro experiments. While there are several X-ray structures of some GPCRs revealing the locations of allosteric sites, especially in chemokine receptors [12,58], clues for allosteric pockets in most other superfamily members, at least so far, could only be derived from indirect experimental evidence or computational methods [59]. While de velopment of the Cryo-EM technique has boosted progress in the field, still less than 10% of available experimentally solved GPCR structures contain allosteric ligands [13].…”

Section: Computational Methods To Study Allostery In Gpcrs-dopamine R...mentioning

confidence: 99%

Allosteric Modulators of Dopamine D2 Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases: Overview, Pharmacology, Structural Aspects and Synthesis

2022

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Allosteric modulation of G protein-coupled receptors (GPCRs) is nowadays a hot topic in medicinal chemistry. Allosteric modulators, i.e., compounds which bind in a receptor site topologically distinct from orthosteric sites, exhibit a number of advantages. They are more selective, safer and display a ceiling effect which prevents overdosing. Allosteric modulators of dopamine D2 receptor are potential drugs against a number of psychiatric and neurological diseases, such as schizophrenia and Parkinson’s disease. In this review, an insightful summary of current research on D2 receptor modulators is presented, ranging from their pharmacology and structural aspects of ligand-receptor interactions to their synthesis.

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Section: Computational Methods To Study Allostery In Gpcrs-dopamine R...mentioning

confidence: 99%

Allosteric Modulators of Dopamine D2 Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases: Overview, Pharmacology, Structural Aspects and Synthesis

2022

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Purinergic Signaling: Impact of GPCR Structures on Rational Drug Design

Salmaso

2020

ChemMedChem

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The purinergic signaling system includes membrane‐bound receptors for extracellular purines and pyrimidines, and enzymes/transporters that regulate receptor activation by endogenous agonists. Receptors include: adenosine (A1, A2A, A2B, and A3) and P2Y (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14) receptors (all GPCRs), as well as P2X receptors (ion channels). Receptor activation, especially accompanying physiological stress or damage, creates a temporal sequence of signaling to counteract this stress and either mobilize (P2Rs) or suppress (ARs) immune responses. Thus, modulation of this large signaling family has broad potential for treating chronic diseases. Experimentally determined structures represent each of the three receptor families. We focus on selective purinergic agonists (A1, A3), antagonists (A3, P2Y14), and allosteric modulators (P2Y1, A3). Examples of applying structure‐based design, including the rational modification of known ligands, are presented for antithrombotic P2Y1R antagonists and anti‐inflammatory P2Y14R antagonists and A3AR agonists. A3AR agonists are a potential, nonaddictive treatment for chronic neuropathic pain.

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Impact of Recently Determined Crystallographic Structures of GPCRs on Drug Discovery

Cited by 2 publications

References 122 publications

Allosteric Modulators of Dopamine D2 Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases: Overview, Pharmacology, Structural Aspects and Synthesis

Allosteric Modulators of Dopamine D2 Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases: Overview, Pharmacology, Structural Aspects and Synthesis

Purinergic Signaling: Impact of GPCR Structures on Rational Drug Design

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