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This corrects the article DOI: 10.1038/nature22800.
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Glucagon-like peptide 1 (GLP-1) regulates glucose homeostasis through the control of insulin release from the pancreas. GLP-1 peptide agonists are efficacious drugs for the treatment of diabetes. To gain insight into the molecular mechanism of action of GLP-1 peptides, here we report the crystal structure of the full-length GLP-1 receptor bound to a truncated peptide agonist. The peptide agonist retains an α-helical conformation as it sits deep within the receptor-binding pocket. The arrangement of the transmembrane helices reveals hallmarks of an active conformation similar to that observed in class A receptors. Guided by this structural information, we design peptide agonists with potent in vivo activity in a mouse model of diabetes.
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Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/química , Péptidos/química , Péptidos/farmacología , Animales , Sitios de Unión , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Humanos , Masculino , Ratones , Modelos Moleculares , Péptidos/metabolismo , Conformación Proteica , Ratas , Receptores de Hormona Liberadora de Corticotropina/química , Receptores de Glucagón/químicaRESUMEN
OBJECTIVE: The current study aimed to examine the relationship between early adaptive schemas and eating disorder symptomatology in adults. METHOD: A cross-sectional, correlational design was used to collect data from 352 females and 36 males aged between 18 and 49 years (M = 25.70, SD = 7.04). Participants completed an online questionnaire, which included The Young Positive Schema Questionnaire (YPSQ), Eating Disorder Examination-Questionnaire (EDE-Q) and demographic measures. RESULTS: Four separate hierarchical multiple regression analyses showed that high levels of Healthy Boundaries and low levels of Optimism significantly predicted lower Restraint, Eating Concern, Shape Concern and Weight Concern scores. Additionally, higher scores in Emotional Openness and Social Belonging significantly predicted lower Eating Concern, while higher scores in Self-Care significantly predicted lower levels of Shape Concern. CONCLUSION: The findings highlight the protective function that certain early adaptive schemas may play in mitigating eating disorder symptomatology. Moreover, the findings allude to potential modifiable therapy targets in the treatment of eating disorders. Further research is needed to investigate any differences in early adaptive schemas between eating disorder diagnoses.
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Trastornos de Alimentación y de la Ingestión de Alimentos , Adulto , Masculino , Femenino , Humanos , Adolescente , Adulto Joven , Persona de Mediana Edad , Autoinforme , Estudios Transversales , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Trastornos de Alimentación y de la Ingestión de Alimentos/terapia , Encuestas y Cuestionarios , PsicometríaRESUMEN
Healthcare providers are at high risk of occupational burnout, which has negative implications on the individual, their profession, the organisation and their patients. Psychologists are particularly susceptible to the repercussions of burnout due to the emotionally draining nature and content of their work. However, research has failed to outline and evaluate effective interventions for burnout within the profession. This study aimed to investigate the treatment effectiveness of burnout through a systematic literature review. Systematic searches of four databases using Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were conducted. A total of 4832 articles were identified, and 15 were included in the final analysis. The search was limited to scholarly and peer-reviewed journals published in the English language, which measured and utilised a form of intervention for the treatment of burnout or stress and included participants within the psychology profession. Interventions identified included mindfulness, training courses, self-care and other therapy-based forms of interventions. Approximately 60% of study participants reported moderate to high levels of stress. Interventions were largely variable in modality, frequency and duration of sessions and follow-up period. Of the 15 studies included within the review, only four measured burnout as an outcome variable, while the others measured stress. Findings of this systematic review indicate that mindfulness-based interventions may be a starting point for reducing stress; however, the most effective intervention for psychologists who have reached burnout is largely unclear. It is recommended that future studies focus on the identification and measurement of burnout, are more rigorously designed and reported and consider peer-based online support approaches.
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PURPOSE: The Young Positive Schema Questionnaire (YPSQ) measures early adaptive schemas (EAS) which could be used to develop positive psychology and schema-based interventions to benefit the treatment of eating disorders (EDs). METHODS: The present study investigated the factor structure of the YPSQ in a sample of 826 participants (18-73 years; n = 753 women) with ED symptomatology (e.g., restricting, binging, and purging). The sample was randomly split into two groups for exploratory and confirmatory factor analyses. Full sample analysis using Pearson correlations was conducted to explore convergent validity of the new YSPQ factor structure with ED symptomatology, emotional regulation, and cognitive flexibility. RESULTS: A nine-factor model was found, demonstrating good fit indices and internal consistency (α = 0.77-0.92). The YPSQ showed an inverse relationship to ED symptomatology and emotional suppression, and a positive relationship with cognitive flexibility and emotion reappraisal. CONCLUSION: Further research is needed to explore the clinical benefits of the YPSQ to identify EAS deficits in individuals with EDs to improve treatment outcomes. LEVEL OF EVIDENCE: Level V, descriptive study.
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Trastornos de Alimentación y de la Ingestión de Alimentos , Humanos , Femenino , Psicometría , Reproducibilidad de los Resultados , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Trastornos de Alimentación y de la Ingestión de Alimentos/terapia , Encuestas y Cuestionarios , EmocionesRESUMEN
Chemokines and their G-protein-coupled receptors play a diverse role in immune defence by controlling the migration, activation and survival of immune cells. They are also involved in viral entry, tumour growth and metastasis and hence are important drug targets in a wide range of diseases. Despite very significant efforts by the pharmaceutical industry to develop drugs, with over 50 small-molecule drugs directed at the family entering clinical development, only two compounds have reached the market: maraviroc (CCR5) for HIV infection and plerixafor (CXCR4) for stem-cell mobilization. The high failure rate may in part be due to limited understanding of the mechanism of action of chemokine antagonists and an inability to optimize compounds in the absence of structural information. CC chemokine receptor type 9 (CCR9) activation by CCL25 plays a key role in leukocyte recruitment to the gut and represents a therapeutic target in inflammatory bowel disease. The selective CCR9 antagonist vercirnon progressed to phase 3 clinical trials in Crohn's disease but efficacy was limited, with the need for very high doses to block receptor activation. Here we report the crystal structure of the CCR9 receptor in complex with vercirnon at 2.8 Å resolution. Remarkably, vercirnon binds to the intracellular side of the receptor, exerting allosteric antagonism and preventing G-protein coupling. This binding site explains the need for relatively lipophilic ligands and describes another example of an allosteric site on G-protein-coupled receptors that can be targeted for drug design, not only at CCR9, but potentially extending to other chemokine receptors.
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Receptores CCR/antagonistas & inhibidores , Receptores CCR/química , Sulfonamidas/química , Sulfonamidas/farmacología , Regulación Alostérica/efectos de los fármacos , Sitio Alostérico/efectos de los fármacos , Sitio Alostérico/genética , Secuencia Conservada , Cristalografía por Rayos X , Citoplasma/metabolismo , Diseño de Fármacos , Proteínas de Unión al GTP Heterotriméricas/antagonistas & inhibidores , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Humanos , Ligandos , Modelos Moleculares , Mutagénesis , Receptores CCR/genética , Receptores CCR5/química , Receptores CXCR4/químicaRESUMEN
OBJECTIVE: Research and theory suggest the aetiological nature and symptomatic profile of eating disorders (EDs) can be explained by multiple factors, including the development of early maladaptive schemas (EMS). Yet, there is lack of consensus regarding the evidence supporting the relationship between EMS and EDs. Therefore, this systematic review aimed to examine existing literature concerning the relationship between different ED diagnoses and EMS to provide a synthesis and evaluation of relevant research. METHOD: A comprehensive literature search of four electronic databases was conducted and studies were included that examined the association between EMS and EDs. Studies were required to use a variant of Young Schema Questionnaire and establish ED diagnosis or symptomology using self-report questionnaires or clinical interview. RESULTS: A total of 29 studies were included in the review. Compared to healthy controls and varying clinical populations, individuals with EDs generally reported significantly higher scores across all EMS except for Entitlement. Furthermore, Unrelenting Standards consistently appeared as a significant EMS across all ED diagnoses whilst Insufficient Self-Control was significantly lower in ED diagnoses with restrictive behaviour compared to diagnoses with binge eating or purging behaviour. DISCUSSION: Research supports significant associations between EMS and EDs, which may contribute to our understanding of ED aetiology, including different diagnostic categories. This review underscores the need for studies to explore more gender and age diverse samples and highlights important implications for practitioners.
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Trastorno por Atracón , Bulimia , Trastornos de Alimentación y de la Ingestión de Alimentos , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Humanos , Encuestas y CuestionariosRESUMEN
The unity of consciousness, or, more precisely, phenomenal unity, is an important property of consciousness and an important area of research in mathematical consciousness science and the scientific study of consciousness. Due to the numerous aspects and complexity of consciousness, the property tends to engender loose or inadequate characterizations. In this article, we introduce the concept and mathematical formulation of model unity. A system has model unity if a single relational model, stretched across the whole system, is optimal. Alternatively, model unity may only be present for subsystems, although there may still be unity at some higher level. As a development in the theory of expected float entropy minimisation, such relational models provide an interpretation of system states and the theory may help to provide insights into questions such as why experience of the visual field is unified and why different people do not have a unified consciousness, for example. This article constitutes a relatively small initial study of model unity. Four investigations were undertaken and are given as examples. A postulate is also given, distilling the foundations of EFE minimisation into a clear statement allowing others to consider whether or not the postulate identifies a self-evident fundamental property of consciousness.
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We present a computational method for full-range interferometric synthetic aperture microscopy (ISAM) under dispersion encoding. With this, one can effectively double the depth range of optical coherence tomography (OCT), whilst dramatically enhancing the spatial resolution away from the focal plane. To this end, we propose a model-based iterative reconstruction (MBIR) method, where ISAM is directly considered in an optimization approach, and we make the discovery that sparsity promoting regularization effectively recovers the full-range signal. Within this work, we adopt an optimal nonuniform discrete fast Fourier transform (NUFFT) implementation of ISAM, which is both fast and numerically stable throughout iterations. We validate our method with several complex samples, scanned with a commercial SD-OCT system with no hardware modification. With this, we both demonstrate full-range ISAM imaging and significantly outperform combinations of existing methods.
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The computational prediction of relative binding free energies is a crucial goal for drug discovery, and G protein-coupled receptors (GPCRs) are arguably the most important drug target class. However, they present increased complexity to model compared to soluble globular proteins. Despite breakthroughs, experimental X-ray crystal and cryo-EM structures are challenging to attain, meaning computational models of the receptor and ligand binding mode are sometimes necessary. This leads to uncertainty in understanding ligand-protein binding induced changes such as, water positioning and displacement, side chain positioning, hydrogen bond networks, and the overall structure of the hydration shell around the ligand and protein. In other words, the very elements that define structure activity relationships (SARs) and are crucial for accurate binding free energy calculations are typically more uncertain for GPCRs. In this work we use free energy perturbation (FEP) to predict the relative binding free energies for ligands of two different GPCRs. We pinpoint the key aspects for success such as the important role of key water molecules, amino acid ionization states, and the benefit of equilibration with specific ligands. Initial calculations following typical FEP setup and execution protocols delivered no correlation with experiment, but we show how results are improved in a logical and systematic way. This approach gave, in the best cases, a coefficient of determination (R2) compared with experiment in the range of 0.6-0.9 and mean unsigned errors compared to experiment of 0.6-0.7 kcal/mol. We anticipate that our findings will be applicable to other difficult-to-model protein ligand data sets and be of wide interest for the community to continue improving FE binding energy predictions.
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Receptores Acoplados a Proteínas G , Entropía , Ligandos , Unión Proteica , TermodinámicaRESUMEN
We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X-ray crystallography to reveal the binding mode of an antagonist series to the A2A adenosine receptor (AR). Eight A2A AR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A2A AR were experimentally determined and investigated through a cycle of ligand-FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X-ray crystallography of the A2A AR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A2A AR, an emerging target in immuno-oncology.
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Antagonistas de Receptores Purinérgicos P1/química , Receptor de Adenosina A2A/química , Termodinámica , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Antagonistas de Receptores Purinérgicos P1/farmacología , Receptor de Adenosina A2A/metabolismoRESUMEN
A series of novel allosteric antagonists of the GLP-1 receptor (GLP-1R), exemplified by HTL26119, are described. SBDD approaches were employed to identify HTL26119, exploiting structural understanding of the allosteric binding site of the closely related Glucagon receptor (GCGR) (Jazayeri et al., 2016) and the homology relationships between GCGR and GLP-1R. The region around residue C3476.36b of the GLP-1R receptor represents a key difference from GCGR and was targeted for selectivity for GLP-1R.
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Receptor del Péptido 1 Similar al Glucagón/antagonistas & inhibidores , Compuestos Heterocíclicos/química , Regulación Alostérica/efectos de los fármacos , Sitio Alostérico , Secuencia de Aminoácidos , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Receptores de Glucagón/antagonistas & inhibidores , Transducción de Señal , Relación Estructura-ActividadRESUMEN
Adenosine receptors are involved in many pathological conditions and are thus promising drug targets. However, developing drugs that target this GPCR subfamily is a challenging task. A number of drug candidates fail due to lack of selectivity which results in unwanted side effects. The extensive structural similarity of adenosine receptors complicates the design of selective ligands. The problem of selective targeting is a general concern in GPCRs, and in this respect adenosine receptors are a prototypical example. Here we use enhanced sampling simulations to decipher the determinants of selectivity of ligands in A2a and A1 adenosine receptors. Our model shows how small differences in the binding pocket and in the water network around the ligand can be leveraged to achieve selectivity.
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Simulación de Dinámica Molecular , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Ligandos , Unión Proteica , Conformación Proteica , Especificidad por SustratoRESUMEN
Over recent decades several mathematical theories of consciousness have been put forward including Karl Friston's Free Energy Principle and Giulio Tononi's Integrated Information Theory. In this article we further investigate theory based on Expected Float Entropy (EFE) minimisation which has been around since 2012. EFE involves a version of Shannon Entropy parameterised by relationships. It turns out that, for systems with bias due to learning, certain choices for the relationship parameters are isolated since giving much lower EFE values than others and, hence, the system defines relationships. It is proposed that, in the context of all these relationships, a brain state acquires meaning in the form of the relational content of the associated experience. EFE minimisation is itself an association learning process and its effectiveness as such is tested in this article. The theory and results are consistent with the proposition of there being a close connection between association learning processes and the emergence of consciousness. Such a theory may explain how the brain defines the content of consciousness up to relationship isomorphism.
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Virtual screening is routinely used to discover new ligands and in particular new ligand chemotypes for G protein-coupled receptors (GPCRs). To prepare for a virtual screen, we often tailor a docking protocol that will enable us to select the best candidates for further screening. To aid this, we created GPCR-Bench, a publically available docking benchmarking set in the spirit of the DUD and DUD-E reference data sets for validation studies, containing 25 nonredundant high-resolution GPCR costructures with an accompanying set of diverse ligands and computational decoy molecules for each target. Benchmarking sets are often used to compare docking protocols; however, it is important to evaluate docking methods not by "retrospective" hit rates but by the actual likelihood that they will produce novel prospective hits. Therefore, docking protocols must not only rank active molecules highly but also produce good poses that a chemist will select for purchase and screening. Currently, no simple objective machine-scriptable function exists that can do this; instead, docking hit lists must be subjectively examined in a consistent way to compare between docking methods. We present here a case study highlighting considerations we feel are of importance when evaluating a method, intended to be useful as a practitioners' guide.
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Simulación del Acoplamiento Molecular , Receptores de Adenosina A2/química , Receptores de Adenosina A2/metabolismo , Benchmarking , Bases de Datos de Proteínas , Evaluación Preclínica de Medicamentos , Ligandos , Conformación Proteica , Interfaz Usuario-Computador , Agua/metabolismoRESUMEN
The residence time of a ligand-protein complex is a crucial aspect in determining biological effect in vivo. Despite its importance, the prediction of ligand koff still remains challenging for modern computational chemistry. We have developed aMetaD, a fast and generally applicable computational protocol to predict ligand-protein unbinding events using a molecular dynamics (MD) method based on adiabatic-bias MD and metadynamics. This physics-based, fully flexible, and pose-dependent ligand scoring function evaluates the maximum energy (RTscore) required to move the ligand from the bound-state energy basin to the next. Unbinding trajectories are automatically analyzed and translated into atomic solvation factor (SF) values representing the water dynamics during the unbinding event. This novel computational protocol was initially tested on two M3 muscarinic receptor and two adenosine A2A receptor antagonists and then evaluated on a test set of 12 CRF1R ligands. The resulting RTscores were used successfully to classify ligands with different residence times. Additionally, the SF analysis was used to detect key differences in the degree of accessibility to water molecules during the predicted ligand unbinding events. The protocol provides actionable working hypotheses that are applicable in a drug discovery program for the rational optimization of ligand binding kinetics.
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Proteínas/química , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Agua/química , Cristalización , Ligandos , Modelos Moleculares , Unión Proteica , Receptores de Hormona Liberadora de Corticotropina/química , Solventes/químicaRESUMEN
Recent efforts in the computational evaluation of the thermodynamic properties of water molecules have resulted in the development of promising new in silico methods to evaluate the role of water in ligand binding. These methods include WaterMap, SZMAP, GRID/CRY probe, and Grand Canonical Monte Carlo simulations. They allow the prediction of the position and relative free energy of the water molecule in the protein active site and the analysis of the perturbation of an explicit water network (WNP) as a consequence of ligand binding. We have for the first time extended these approaches toward the prediction of kinetics for small molecules and of relative free energy of binding with a focus on the perturbation of the water network and application to large diverse data sets. Our results support a qualitative correlation between the residence time of 12 related triazine adenosine A(2A) receptor antagonists and the number and position of high energy trapped solvent molecules. From a quantitative viewpoint, we successfully applied these computational techniques as an implicit solvent alternative, in linear combination with a molecular mechanics force field, to predict the relative ligand free energy of binding (WNP-MMSA). The applicability of this linear method, based on the thermodynamics additivity principle, did not extend to 375 diverse A(2A) receptor antagonists. However, a fast but effective method could be enabled by replacing the linear approach with a machine learning technique using probabilistic classification trees, which classified the binding affinity correctly for 90% of the ligands in the training set and 67% in the test set.
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Antagonistas del Receptor de Adenosina A2/metabolismo , Modelos Moleculares , Receptor de Adenosina A2A/metabolismo , Agua/química , Antagonistas del Receptor de Adenosina A2/química , Algoritmos , Cinética , Ligandos , Método de Montecarlo , Probabilidad , Unión Proteica , Conformación Proteica , Receptor de Adenosina A2A/química , TermodinámicaRESUMEN
INTRODUCTION: Obtaining a fusion, especially to the sacrum for adult deformity correction remains a challenge. Prior to modern fixation techniques, the reported fusion rates for adult scoliotic deformities were low. However sacropelvic fixation techniques for adult deformity continue to evolve. As a result, modern day pelvic fixation techniques have improved fusion rates at the base of long constructs. The purpose of this article is to discuss the history, indications, and modern fixation techniques for pelvic fixation in the surgical management of adult scoliosis patients. METHODS: We searched PUBMED using the search terms pelvic fixation, deformity, lumbopelvic, sacropelvic, and iliac fixation. Linkage or association studies published in English and available full-text were analyzed specifically regarding techniques and innovations in pelvic fixation. RESULTS: Sacropelvic fixation should be considered in any patient with a long construct ending in the sacrum, those patients with associated risk factors for loss of distal fixation or high risk for pseudarthrosis at L5-S1, and those undergoing three column osteotomies or vertebral body resections in the low lumbar spine. Current pelvic fixation techniques with iliac screws, multiple screw/rod constructs, and S2-alar-iliac screws are all viable techniques for achieving pelvic fixation. CONCLUSIONS: There is growing evidence that pelvic fixation may become the standard for obtaining long fusions in adult scoliosis. Although technically challenging, in selected cases the use of four pelvic screws and/or four rods across the lumbosacral pelvis can help address pseudarthroses, implant breakage, and screw pullout secondary to osteoporosis. Ultimately, indications and techniques should be individualized to the patient and based on surgeon preference and experience.
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Huesos Pélvicos/cirugía , Sacro/cirugía , Escoliosis/cirugía , Fusión Vertebral/métodos , Humanos , Fusión Vertebral/instrumentaciónRESUMEN
The role of the mechanical environment in defining tissue function, development and growth has been shown to be fundamental. Assessment of the changes in stiffness of tissue matrices at multiple scales has relied mostly on invasive and often specialist equipment such as AFM or mechanical testing devices poorly suited to the cell culture workflow.In this paper, we have developed a unbiased passive optical coherence elastography method, exploiting ambient vibrations in the sample that enables real-time noninvasive quantitative profiling of cells and tissues. We demonstrate a robust method that decouples optical scattering and mechanical properties by actively compensating for scattering associated noise bias and reducing variance. The efficiency for the method to retrieve ground truth is validated in silico and in vitro, and exemplified for key applications such as time course mechanical profiling of bone and cartilage spheroids, tissue engineering cancer models, tissue repair models and single cell. Our method is readily implementable with any commercial optical coherence tomography system without any hardware modifications, and thus offers a breakthrough in on-line tissue mechanical assessment of spatial mechanical properties for organoids, soft tissues and tissue engineering.
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Diagnóstico por Imagen de Elasticidad , Vibración , Diagnóstico por Imagen de Elasticidad/métodos , Tomografía de Coherencia Óptica/métodos , Cartílago , OrganoidesRESUMEN
A series of macrocyclic calcitonin gene-related peptide (CGRP) receptor antagonists identified using structure-based design principles, exemplified by HTL0028016 (1) and HTL0028125 (2), is described. Structural characterization by X-ray crystallography of the interaction of two of the macrocycle antagonists with the CGRP receptor ectodomain is described, along with structure-activity relationships associated with point changes to the macrocyclic antagonists. The identification of non-peptidic/natural product-derived, macrocyclic ligands for a G protein coupled receptor (GPCR) is noteworthy.