Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 71
Filtrar
1.
Cell ; 186(24): 5203-5219, 2023 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-37995655

RESUMEN

Opioids are used for pain management despite the side effects that contribute to the opioid crisis. The pursuit of non-addictive opioid analgesics remains unattained due to the unresolved intricacies of opioid actions, receptor signaling cascades, and neuronal plasticity. Advancements in structural, molecular, and computational tools illuminate the dynamic interplay between opioids and opioid receptors, as well as the molecular determinants of signaling pathways, which are potentially interlinked with pharmacological responses. Here, we review the molecular basis of opioid receptor signaling with a focus on the structures of opioid receptors bound to endogenous peptides or pharmacological agents. These insights unveil specific interactions that dictate ligand selectivity and likely their distinctive pharmacological profiles. Biochemical analysis further unveils molecular features governing opioid receptor signaling. Simultaneously, the synergy between computational biology and medicinal chemistry continues to expedite the discovery of novel chemotypes with the promise of yielding more efficacious and safer opioid compounds.


Asunto(s)
Analgésicos Opioides , Receptores Opioides , Transducción de Señal , Humanos , Analgésicos Opioides/farmacología , Animales
2.
Annu Rev Biochem ; 90: 739-761, 2021 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-33756098

RESUMEN

Opioids such as morphine and oxycodone are analgesics frequently prescribed for the treatment of moderate or severe pain. Unfortunately, these medications are associated with exceptionally high abuse potentials and often cause fatal side effects, mainly through the µ-opioid receptor (MOR). Efforts to discover novel, safer, and more efficacious analgesics targeting MOR have encountered challenges. In this review, we summarize alternative strategies and targets that could be used to develop safer nonopioid analgesics. A molecular understanding of G protein-coupled receptor activation and signaling has illuminated not only the complexities of receptor pharmacology but also the potential for pathway-selective agonists and allosteric modulators as safer medications. The availability of structures of pain-related receptors, in combination with high-throughput computational tools, has accelerated the discovery of multitarget ligands with promising pharmacological profiles. Emerging clinical evidence also supports the notion that drugs targeting peripheral opioid receptors have potential as improved analgesic agents.


Asunto(s)
Analgésicos no Narcóticos/química , Analgésicos no Narcóticos/farmacología , Receptores Opioides/química , Receptores Opioides/metabolismo , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/farmacología , Animales , Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Ligandos , Receptores Acoplados a Proteínas G/metabolismo
3.
Cell ; 182(6): 1574-1588.e19, 2020 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-32946782

RESUMEN

Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions-both therapeutic and hallucinogenic-are not understood, although activation of the 5-HT2A serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH-a prototypical hallucinogen-in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders.


Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gq-G11/química , Alucinógenos/química , Receptor de Serotonina 5-HT2A/química , Receptor de Serotonina 5-HT2A/metabolismo , Animales , Microscopía por Crioelectrón , Cristalografía por Rayos X , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Expresión Génica , Células HEK293 , Alucinógenos/farmacología , Alucinógenos/uso terapéutico , Humanos , Ligandos , Dietilamida del Ácido Lisérgico/química , Dietilamida del Ácido Lisérgico/farmacología , Metiotepina/química , Metiotepina/metabolismo , Modelos Químicos , Mutación , Conformación Proteica en Hélice alfa , Receptor de Serotonina 5-HT2A/genética , Proteínas Recombinantes , Serotonina/metabolismo , Spodoptera
4.
Cell ; 172(4): 719-730.e14, 2018 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-29398112

RESUMEN

Drugs frequently require interactions with multiple targets-via a process known as polypharmacology-to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 Å and 2.7 Å, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs.


Asunto(s)
Ergotamina/química , Receptor de Serotonina 5-HT2C/química , Ritanserina/química , Agonistas del Receptor de Serotonina 5-HT2/química , Antagonistas del Receptor de Serotonina 5-HT2/química , Células HEK293 , Humanos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Dominios Proteicos , Receptor de Serotonina 5-HT2C/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Relación Estructura-Actividad , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Trastornos Relacionados con Sustancias/metabolismo
5.
Cell ; 172(1-2): 55-67.e15, 2018 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-29307491

RESUMEN

The κ-opioid receptor (KOP) mediates the actions of opioids with hallucinogenic, dysphoric, and analgesic activities. The design of KOP analgesics devoid of hallucinatory and dysphoric effects has been hindered by an incomplete structural and mechanistic understanding of KOP agonist actions. Here, we provide a crystal structure of human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active-state-stabilizing nanobody. Comparisons between inactive- and active-state opioid receptor structures reveal substantial conformational changes in the binding pocket and intracellular and extracellular regions. Extensive structural analysis and experimental validation illuminate key residues that propagate larger-scale structural rearrangements and transducer binding that, collectively, elucidate the structural determinants of KOP pharmacology, function, and biased signaling. These molecular insights promise to accelerate the structure-guided design of safer and more effective κ-opioid receptor therapeutics.


Asunto(s)
Simulación del Acoplamiento Molecular , Receptores Opioides kappa/química , Analgésicos/química , Analgésicos/farmacología , Animales , Sitios de Unión , Células HEK293 , Humanos , Simulación de Dinámica Molecular , Morfinanos/química , Morfinanos/farmacología , Unión Proteica , Estabilidad Proteica , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismo , Células Sf9 , Spodoptera
6.
Cell ; 168(3): 377-389.e12, 2017 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-28129538

RESUMEN

The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD's key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT2BR and 5-HT2AR-a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD's slow binding kinetics may be due to a "lid" formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD's binding kinetics and selectively dampens LSD-mediated ß-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD's actions at human serotonin receptors. PAPERCLIP.


Asunto(s)
Dietilamida del Ácido Lisérgico/química , Receptor de Serotonina 5-HT2B/química , Arrestina/química , Cristalografía por Rayos X , Humanos , Cinética , Modelos Químicos , Simulación de Dinámica Molecular
7.
Nature ; 629(8011): 474-480, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38600384

RESUMEN

The µ-opioid receptor (µOR) is an important target for pain management1 and molecular understanding of drug action on µOR will facilitate the development of better therapeutics. Here we show, using double electron-electron resonance and single-molecule fluorescence resonance energy transfer, how ligand-specific conformational changes of µOR translate into a broad range of intrinsic efficacies at the transducer level. We identify several conformations of the cytoplasmic face of the receptor that interconvert on different timescales, including a pre-activated conformation that is capable of G-protein binding, and a fully activated conformation that markedly reduces GDP affinity within the ternary complex. Interaction of ß-arrestin-1 with the µOR core binding site appears less specific and occurs with much lower affinity than binding of Gi.


Asunto(s)
Ligandos , Conformación Proteica , Receptores Opioides mu , Humanos , beta-Arrestina 1/química , beta-Arrestina 1/metabolismo , Sitios de Unión , Transferencia Resonante de Energía de Fluorescencia , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/química , Guanosina Difosfato/metabolismo , Guanosina Difosfato/química , Modelos Moleculares , Unión Proteica , Receptores Opioides mu/metabolismo , Receptores Opioides mu/química , Imagen Individual de Molécula
8.
Nature ; 631(8021): 686-693, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38961287

RESUMEN

The µ-opioid receptor (µOR) is a well-established target for analgesia1, yet conventional opioid receptor agonists cause serious adverse effects, notably addiction and respiratory depression. These factors have contributed to the current opioid overdose epidemic driven by fentanyl2, a highly potent synthetic opioid. µOR negative allosteric modulators (NAMs) may serve as useful tools in preventing opioid overdose deaths, but promising chemical scaffolds remain elusive. Here we screened a large DNA-encoded chemical library against inactive µOR, counter-screening with active, G-protein and agonist-bound receptor to 'steer' hits towards conformationally selective modulators. We discovered a NAM compound with high and selective enrichment to inactive µOR that enhances the affinity of the key opioid overdose reversal molecule, naloxone. The NAM works cooperatively with naloxone to potently block opioid agonist signalling. Using cryogenic electron microscopy, we demonstrate that the NAM accomplishes this effect by binding a site on the extracellular vestibule in direct contact with naloxone while stabilizing a distinct inactive conformation of the extracellular portions of the second and seventh transmembrane helices. The NAM alters orthosteric ligand kinetics in therapeutically desirable ways and works cooperatively with low doses of naloxone to effectively inhibit various morphine-induced and fentanyl-induced behavioural effects in vivo while minimizing withdrawal behaviours. Our results provide detailed structural insights into the mechanism of negative allosteric modulation of the µOR and demonstrate how this can be exploited in vivo.


Asunto(s)
Analgésicos Opioides , Evaluación Preclínica de Medicamentos , Naloxona , Receptores Opioides mu , Bibliotecas de Moléculas Pequeñas , Animales , Humanos , Masculino , Ratones , Regulación Alostérica/efectos de los fármacos , Analgésicos Opioides/antagonistas & inhibidores , Analgésicos Opioides/farmacología , Sitios de Unión/efectos de los fármacos , Microscopía por Crioelectrón , Fentanilo/antagonistas & inhibidores , Fentanilo/farmacología , Cinética , Ligandos , Modelos Moleculares , Morfina/antagonistas & inhibidores , Morfina/farmacología , Naloxona/administración & dosificación , Naloxona/química , Naloxona/metabolismo , Naloxona/farmacología , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/química , Antagonistas de Narcóticos/metabolismo , Antagonistas de Narcóticos/farmacología , Sobredosis de Opiáceos/tratamiento farmacológico , Conformación Proteica/efectos de los fármacos , Estabilidad Proteica/efectos de los fármacos , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Células Sf9 , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Ratones Endogámicos C57BL
9.
Nature ; 617(7960): 417-425, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37138078

RESUMEN

The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders1. However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects2. The initiation of KOR signalling requires the Gi/o-family proteins including the conventional (Gi1, Gi2, Gi3, GoA and GoB) and nonconventional (Gz and Gg) subtypes. How hallucinogens exert their actions through KOR and how KOR determines G-protein subtype selectivity are not well understood. Here we determined the active-state structures of KOR in a complex with multiple G-protein heterotrimers-Gi1, GoA, Gz and Gg-using cryo-electron microscopy. The KOR-G-protein complexes are bound to hallucinogenic salvinorins or highly selective KOR agonists. Comparisons of these structures reveal molecular determinants critical for KOR-G-protein interactions as well as key elements governing Gi/o-family subtype selectivity and KOR ligand selectivity. Furthermore, the four G-protein subtypes display an intrinsically different binding affinity and allosteric activity on agonist binding at KOR. These results provide insights into the actions of opioids and G-protein-coupling specificity at KOR and establish a foundation to examine the therapeutic potential of pathway-selective agonists of KOR.


Asunto(s)
Microscopía por Crioelectrón , Proteínas de Unión al GTP Heterotriméricas , Ligandos , Receptores Opioides kappa , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacología , Receptores Opioides kappa/química , Receptores Opioides kappa/metabolismo , Receptores Opioides kappa/ultraestructura , Transducción de Señal , Proteínas de Unión al GTP Heterotriméricas/química , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Proteínas de Unión al GTP Heterotriméricas/ultraestructura , Especificidad por Sustrato , Regulación Alostérica/efectos de los fármacos , Alucinógenos/metabolismo , Alucinógenos/farmacología
10.
Nature ; 613(7945): 767-774, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36450356

RESUMEN

Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose1. Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site2 found in µOR3 and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp2.50 residue in the Na+ site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at Gi subtypes and show strongly reduced arrestin recruitment-one (C6 guano) also shows the lowest Gz efficacy among the panel of µOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed µOR-dependent antinociception with attenuated adverse effects, supporting the µOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for Gi, Go and Gz subtypes and arrestins, thus modulating their in vivo pharmacology.


Asunto(s)
Diseño de Fármacos , Fentanilo , Morfinanos , Receptores Opioides mu , Animales , Ratones , Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Arrestinas/metabolismo , Microscopía por Crioelectrón , Fentanilo/análogos & derivados , Fentanilo/química , Fentanilo/metabolismo , Ligandos , Morfinanos/química , Morfinanos/metabolismo , Receptores Opioides mu/agonistas , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Receptores Opioides mu/ultraestructura , Sitios de Unión , Nocicepción
11.
Nature ; 610(7932): 582-591, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36171289

RESUMEN

There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally1-4. Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines-a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C-H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization5-7. Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT2A receptor (5-HT2AR) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT2A or the 5-HT2B receptors. Structure-based optimization led to the 5-HT2AR agonists (R)-69 and (R)-70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HT2AR agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT2AR. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HT2AR agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered.


Asunto(s)
Antidepresivos , Pirrolidinas , Receptor de Serotonina 5-HT2A , Animales , Ratones , Antidepresivos/farmacología , Microscopía por Crioelectrón , Fluoxetina/administración & dosificación , Fluoxetina/farmacología , Alucinógenos/administración & dosificación , Alucinógenos/farmacología , Ligandos , Pirrolidinas/administración & dosificación , Pirrolidinas/farmacología , Receptor de Serotonina 5-HT2A/metabolismo , Bibliotecas de Moléculas Pequeñas
12.
Nature ; 579(7800): 609-614, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32040955

RESUMEN

The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT1 and MT2. Circadian release of melatonin at night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light-dark cycle1-4. The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep5,6 and depression1-4,7-9. Despite their importance, few in vivo active MT1-selective ligands have been reported2,8,10-12, hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT1 crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT1 inverse agonists-which were topologically unrelated to previously explored chemotypes-that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT1-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT1- but not in MT2-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT1-selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries.


Asunto(s)
Ritmo Circadiano/fisiología , Ligandos , Receptores de Melatonina/agonistas , Receptores de Melatonina/metabolismo , Animales , Ritmo Circadiano/efectos de los fármacos , Oscuridad , Evaluación Preclínica de Medicamentos , Agonismo Inverso de Drogas , Femenino , Humanos , Luz , Masculino , Ratones , Ratones Noqueados , Simulación del Acoplamiento Molecular , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT1/deficiencia , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/agonistas , Receptor de Melatonina MT2/deficiencia , Receptor de Melatonina MT2/genética , Receptor de Melatonina MT2/metabolismo , Receptores de Melatonina/deficiencia , Receptores de Melatonina/genética , Bibliotecas de Moléculas Pequeñas/farmacología , Especificidad por Sustrato/genética
13.
Nat Chem Biol ; 19(4): 423-430, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36411392

RESUMEN

Drugs targeting the µ-opioid receptor (µOR) are the most effective analgesics available but are also associated with fatal respiratory depression through a pathway that remains unclear. Here we investigated the mechanistic basis of action of lofentanil (LFT) and mitragynine pseudoindoxyl (MP), two µOR agonists with different safety profiles. LFT, one of the most lethal opioids, and MP, a kratom plant derivative with reduced respiratory depression in animal studies, exhibited markedly different efficacy profiles for G protein subtype activation and ß-arrestin recruitment. Cryo-EM structures of µOR-Gi1 complex with MP (2.5 Å) and LFT (3.2 Å) revealed that the two ligands engage distinct subpockets, and molecular dynamics simulations showed additional differences in the binding site that promote distinct active-state conformations on the intracellular side of the receptor where G proteins and ß-arrestins bind. These observations highlight how drugs engaging different parts of the µOR orthosteric pocket can lead to distinct signaling outcomes.


Asunto(s)
Analgésicos Opioides , Transducción de Señal , Animales , beta-Arrestinas/metabolismo , Analgésicos Opioides/química , Analgésicos Opioides/farmacología , Proteínas de Unión al GTP/metabolismo , Sitios de Unión
14.
Nature ; 566(7743): 224-229, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30728502

RESUMEN

Despite intense interest in expanding chemical space, libraries containing hundreds-of-millions to billions of diverse molecules have remained inaccessible. Here we investigate structure-based docking of 170 million make-on-demand compounds from 130 well-characterized reactions. The resulting library is diverse, representing over 10.7 million scaffolds that are otherwise unavailable. For each compound in the library, docking against AmpC ß-lactamase (AmpC) and the D4 dopamine receptor were simulated. From the top-ranking molecules, 44 and 549 compounds were synthesized and tested for interactions with AmpC and the D4 dopamine receptor, respectively. We found a phenolate inhibitor of AmpC, which revealed a group of inhibitors without known precedent. This molecule was optimized to 77 nM, which places it among the most potent non-covalent AmpC inhibitors known. Crystal structures of this and other AmpC inhibitors confirmed the docking predictions. Against the D4 dopamine receptor, hit rates fell almost monotonically with docking score, and a hit-rate versus score curve predicted that the library contained 453,000 ligands for the D4 dopamine receptor. Of 81 new chemotypes discovered, 30 showed submicromolar activity, including a 180-pM subtype-selective agonist of the D4 dopamine receptor.


Asunto(s)
Agonistas de Dopamina/química , Agonistas de Dopamina/aislamiento & purificación , Simulación del Acoplamiento Molecular/métodos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/aislamiento & purificación , Inhibidores de beta-Lactamasas/química , Inhibidores de beta-Lactamasas/aislamiento & purificación , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/química , Cristalografía por Rayos X , Humanos , Ligandos , Aprendizaje Automático , Observación , Receptores de Dopamina D4/agonistas , Receptores de Dopamina D4/química , Receptores de Dopamina D4/metabolismo , beta-Lactamasas/química
15.
Nature ; 555(7695): 269-273, 2018 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-29466326

RESUMEN

Dopamine is a neurotransmitter that has been implicated in processes as diverse as reward, addiction, control of coordinated movement, metabolism and hormonal secretion. Correspondingly, dysregulation of the dopaminergic system has been implicated in diseases such as schizophrenia, Parkinson's disease, depression, attention deficit hyperactivity disorder, and nausea and vomiting. The actions of dopamine are mediated by a family of five G-protein-coupled receptors. The D2 dopamine receptor (DRD2) is the primary target for both typical and atypical antipsychotic drugs, and for drugs used to treat Parkinson's disease. Unfortunately, many drugs that target DRD2 cause serious and potentially life-threatening side effects due to promiscuous activities against related receptors. Accordingly, a molecular understanding of the structure and function of DRD2 could provide a template for the design of safer and more effective medications. Here we report the crystal structure of DRD2 in complex with the widely prescribed atypical antipsychotic drug risperidone. The DRD2-risperidone structure reveals an unexpected mode of antipsychotic drug binding to dopamine receptors, and highlights structural determinants that are essential for the actions of risperidone and related drugs at DRD2.


Asunto(s)
Antipsicóticos/química , Antipsicóticos/metabolismo , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismo , Risperidona/química , Risperidona/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Cinética , Ligandos , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/química , Receptores de Dopamina D3/metabolismo , Receptores de Dopamina D4/química , Receptores de Dopamina D4/metabolismo
16.
Sensors (Basel) ; 23(22)2023 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-38005509

RESUMEN

The leaf area index (LAI) played a crucial role in ecological, hydrological, and climate models. The normalized difference vegetation index (NDVI) has been a widely used tool for LAI estimation. However, the NDVI quickly saturates in dense vegetation and is susceptible to soil background interference in sparse vegetation. We proposed a multi-angular NDVI (MAVI) to enhance LAI estimation using tower-based multi-angular observations, aiming to minimize the interference of soil background and saturation effects. Our methodology involved collecting continuous tower-based multi-angular reflectance and the LAI over a three-year period in maize cropland. Then we proposed the MAVI based on an analysis of how canopy reflectance varies with solar zenith angle (SZA). Finally, we quantitatively evaluated the MAVI's performance in LAI retrieval by comparing it to eight other vegetation indices (VIs). Statistical tests revealed that the MAVI exhibited an improved curvilinear relationship with the LAI when the NDVI is corrected using multi-angular observations (R2 = 0.945, RMSE = 0.345, rRMSE = 0.147). Furthermore, the MAVI-based model effectively mitigated soil background effects in sparse vegetation (R2 = 0.934, RMSE = 0.155, rRMSE = 0.157). Our findings demonstrated the utility of tower-based multi-angular spectral observations in LAI retrieval, having the potential to provide continuous data for validating space-borne LAI products. This research significantly expanded the potential applications of multi-angular observations.


Asunto(s)
Suelo , Zea mays , Hojas de la Planta
17.
Nat Chem Biol ; 16(8): 841-849, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32367019

RESUMEN

G-protein-coupled receptors (GPCRs) remain major drug targets, despite our incomplete understanding of how they signal through 16 non-visual G-protein signal transducers (collectively named the transducerome) to exert their actions. To address this gap, we have developed an open-source suite of 14 optimized bioluminescence resonance energy transfer (BRET) Gαßγ biosensors (named TRUPATH) to interrogate the transducerome with single pathway resolution in cells. Generated through exhaustive protein engineering and empirical testing, the TRUPATH suite of Gαßγ biosensors includes the first Gα15 and GαGustducin probes. In head-to-head studies, TRUPATH biosensors outperformed first-generation sensors at multiple GPCRs and in different cell lines. Benchmarking studies with TRUPATH biosensors recapitulated previously documented signaling bias and revealed new coupling preferences for prototypic and understudied GPCRs with potential in vivo relevance. To enable a greater understanding of GPCR molecular pharmacology by the scientific community, we have made TRUPATH biosensors easily accessible as a kit through Addgene.


Asunto(s)
Técnicas Biosensibles/instrumentación , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/fisiología , Técnicas Biosensibles/métodos , Proteínas de Unión al GTP/metabolismo , Células HEK293 , Humanos , Ingeniería de Proteínas/métodos , Transducción de Señal
18.
Sensors (Basel) ; 22(10)2022 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-35632122

RESUMEN

In this article, we employed a satellite-enabled Internet of Remote Things (IoRT) network as a promising solution to retrieve data in the most remote areas of interest, where public networks are absent. This article presents a system network based on the satellite-enabled IoRT, a new paradigm that defines a network where each environmental monitoring device can autonomously establish a network with a remote data center. The Xingyun satellite constellation was employed for data retrieval on the Tibetan Plateau (TP). The monitoring system was mainly composed of a ground Internet of Things (IoT) terminal that was built with satellite transceivers, environmental monitoring devices, and system software. We deployed five of these newly developed terminals in harsh areas to monitor environmental variables, and accordingly, air temperature and relative humidity, precipitation, snow depth, land surface temperature, tree stemflow rate, and photosynthetically active radiation were retrieved with the satellite-enabled IoRT network. Field experiments were conducted to evaluate the performance of the proposed system network, and the results indicated that the average time delay with and without the packet creation mode reached 32 and 32.7 s, respectively, and the average packet loss rate with and without the packet creation mode reached 5.63% and 4.48%, respectively. The successful implementation of the satellite-enabled IoRT network for the rapid retrieval of monitoring data in remote glacier, forestland, and canyon areas at very high altitudes on the TP provides an entirely new and revolutionary data retrieval means for backhauling data from remote areas of interest.

19.
Molecules ; 27(3)2022 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-35163856

RESUMEN

In our society today, pain has become a main source of strain on most individuals. It is crucial to develop novel treatments against pain while focusing on decreasing their adverse effects. Throughout the extent of development for new pain therapies, the nociceptin/orphanin FQ receptor (NOP receptor) has appeared to be an encouraging focal point. Concentrating on NOP receptor to treat chronic pain with limited range of unwanted effects serves as a suitable alternative to prototypical opioid morphine that could potentially lead to life-threatening effects caused by respiratory depression in overdose, as well as generate abuse and addiction. In addition to these harmful effects, the uprising opioid epidemic is responsible for becoming one of the most disastrous public health issues in the US. In this article, the contributing molecular and cellular structure in controlling the cellular trafficking of NOP receptor and studies that support the role of NOP receptor and its ligands in pain management are reviewed.


Asunto(s)
Antagonistas de Narcóticos/farmacología , Dolor/tratamiento farmacológico , Receptores Opioides/química , Animales , Humanos , Ligandos , Dolor/metabolismo , Dolor/patología , Receptores Opioides/metabolismo , Receptor de Nociceptina
20.
Biochemistry ; 60(18): 1401-1412, 2021 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-33186495

RESUMEN

Pain is an essential protective mechanism that the body uses to alert or prevent further damage. Pain sensation is a complex event involving perception, transmission, processing, and response. Neurons at different levels (peripheral, spinal cord, and brain) are responsible for these pro- or antinociceptive activities to ensure an appropriate response to external stimuli. The terminals of these neurons, both in the peripheral endings and in the synapses, are equipped with G protein-coupled receptors (GPCRs), voltage- and ligand-gated ion channels that sense structurally diverse stimuli and inhibitors of neuronal activity. This review will focus on the largest class of sensory proteins, the GPCRs, as they are distributed throughout ascending and descending neurons and regulate activity at each step during pain transmission. GPCR activation also directly or indirectly controls the function of co-localized ion channels. The levels and types of some GPCRs are significantly altered in different pain models, especially chronic pain states, emphasizing that these molecules could be new targets for therapeutic intervention in chronic pain.


Asunto(s)
Analgésicos/farmacología , Dolor Crónico/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Neuronas/efectos de los fármacos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Analgésicos/química , Animales , Humanos , Neuronas/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA