ArticleCell research2014
Structures and mechanism for the design of highly potent glucocorticoids.
Article in Cell research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed.
- Balancing inflammation under stress: glucocorticoid regulation of innate immune pathways.Bioscience reports · 2026Review
- Computational and experimental insights into the interaction of the seaweed-derived steroidal metabolite 11α-hydroxyprogesterone with the glucocorticoid receptor.Computational and structural biotechnology journal · 2026Article
- Comparative quantum chemical analysis of dexamethasone and hydrocortisone: electronic structure, and reactivity indices using DFT.Journal of molecular modeling · 2025Article
- The multimerization pathway of the glucocorticoid receptor.Nucleic acids research · 2025Article
- Effects of glucocorticoid receptor activation on gene expression and antiviral responses in Atlantic salmon (Salmo salar L.) red blood cells.Veterinary research · 2025Article
- Incorporation of Mometasone Furoate into a Cyclodextrin Metal-Organic Framework to Optimize Nasal Administration.Pharmaceutics · 2025Article
- Nuclear hormone receptors control fundamental processes of human fetal neurodevelopment: Basis for endocrine disruption assessment.Environment international · 2025Article
- Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host.Cancer cell · 2025Article
- Tau is a receptor with low affinity for glucocorticoids and is required for glucocorticoid-induced bone loss.Cell research · 2025Article
- Bilayered skin equivalent mimicking psoriasis as predictive tool for preclinical treatment studies.Communications biology · 2024Article
- Accelerating reliable multiscale quantum refinement of protein-drug systems enabled by machine learning.Nature communications · 2024Article
- Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host.bioRxiv : the preprint server for biology · 2024Article
- Hypoglycemic Activity of Rice Resistant-Starch Metabolites: A Mechanistic Network Pharmacology and In Vitro Approach.Metabolites · 2024Article
- Glucocorticoids, their uses, sexual dimorphisms, and diseases: new concepts, mechanisms, and discoveries.Physiological reviews · 2024Review
- Biotransformation of ΔInternational journal of molecular sciences · 2023Article
- Review
- Identification of an Evolutionarily Conserved Allosteric Network in Steroid Receptors.Journal of chemical information and modeling · 2023Article
- The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities.Nucleic acids research · 2022Article
- Investigation of the Influence of Various Functional Groups on the Dynamics of Glucocorticoids.ACS omega · 2022Article
- Dexamethasone-Induced Adipose Tissue Redistribution and Metabolic Changes: Is Gene Expression the Main Factor? An Animal Model of Chronic Hypercortisolism.Biomedicines · 2022Article
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
The evolution of glucocorticoid drugs was driven by the demand of lowering the unwanted side effects, while keeping the beneficial anti-inflammatory effects. Potency is an important aspect of this evolution as many undesirable side effects are associated with use of high-dose glucocorticoids. The side effects can be minimized by highly potent glucocorticoids that achieve the same treatment effects at lower doses. This demand propelled the continuous development of synthetic glucocorticoids with increased potencies, but the structural basis of their potencies is poorly understood. To determine the mechanisms underlying potency, we solved the X-ray structures of the glucocorticoid receptor (GR) ligand-binding domain (LBD) bound to its endogenous ligand, cortisol, which has relatively low potency, and a highly potent synthetic glucocorticoid, mometasone furoate (MF). The cortisol-bound GR LBD revealed that the flexibility of the C1-C2 single bond in the steroid A ring is primarily responsible for the low affinity of cortisol to GR. In contrast, we demonstrate that the very high potency of MF is achieved by its C-17α furoate group completely filling the ligand-binding pocket, thus providing additional anchor contacts for high-affinity binding. A single amino acid in the ligand-binding pocket, Q642, plays a discriminating role in ligand potency between MF and cortisol. Structure-based design led to synthesis of several novel glucocorticoids with much improved potency and efficacy. Together, these results reveal key structural mechanisms of glucocorticoid potency and provide a rational basis for developing novel highly potent glucocorticoids.
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Registered trials
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