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1.
ACS Chem Biol ; 17(10): 2744-2752, 2022 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-36149353

RESUMEN

Recently determined structures of class C G protein-coupled receptors (GPCRs) revealed the location of allosteric binding sites and opened new opportunities for the discovery of novel modulators. In this work, molecular docking screens for allosteric modulators targeting the metabotropic glutamate receptor 5 (mGlu5) were performed. The mGlu5 receptor is activated by the main excitatory neurotransmitter of the nervous central system, L-glutamate, and mGlu5 receptor activity can be allosterically modulated by negative or positive allosteric modulators. The mGlu5 receptor is a promising target for the treatment of psychiatric and neurodegenerative diseases, and several allosteric modulators of this GPCR have been evaluated in clinical trials. Chemical libraries containing fragment- (1.6 million molecules) and lead-like (4.6 million molecules) compounds were docked to an allosteric binding site of mGlu5 identified in X-ray crystal structures. Among the top-ranked compounds, 59 fragments and 59 lead-like compounds were selected for experimental evaluation. Of these, four fragment- and seven lead-like compounds were confirmed to bind to the allosteric site with affinities ranging from 0.43 to 8.6 µM, corresponding to a hit rate of 9%. The four compounds with the highest affinities were demonstrated to be negative allosteric modulators of mGlu5 signaling in functional assays. The results demonstrate that virtual screens of fragment- and lead-like chemical libraries have complementary advantages and illustrate how access to high-resolution structures of GPCRs in complex with allosteric modulators can accelerate lead discovery.


Asunto(s)
Receptor del Glutamato Metabotropico 5 , Bibliotecas de Moléculas Pequeñas , Receptor del Glutamato Metabotropico 5/metabolismo , Regulación Alostérica , Simulación del Acoplamiento Molecular , Bibliotecas de Moléculas Pequeñas/farmacología , Ligandos , Ácido Glutámico , Sitio Alostérico , Receptores Acoplados a Proteínas G
2.
Nature ; 494(7436): 185-94, 2013 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-23407534

RESUMEN

G-protein-coupled receptors (GPCRs) are physiologically important membrane proteins that sense signalling molecules such as hormones and neurotransmitters, and are the targets of several prescribed drugs. Recent exciting developments are providing unprecedented insights into the structure and function of several medically important GPCRs. Here, through a systematic analysis of high-resolution GPCR structures, we uncover a conserved network of non-covalent contacts that defines the GPCR fold. Furthermore, our comparative analysis reveals characteristic features of ligand binding and conformational changes during receptor activation. A holistic understanding that integrates molecular and systems biology of GPCRs holds promise for new therapeutics and personalized medicine.


Asunto(s)
Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Animales , Sitios de Unión , Cristalografía por Rayos X , Humanos , Ligandos , Conformación Proteica , Pliegue de Proteína , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Transducción de Señal
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