A Comprehensive Analysis of Fibromyalgia and the Role of the Endogenous Opioid System

Biomedicines, Год журнала: 2025, Номер 13(1), С. 165 - 165

Опубликована: Янв. 11, 2025

Fibromyalgia represents a chronic pain disorder characterized by musculoskeletal pain, fatigue, and cognitive impairments. The exact mechanisms underlying fibromyalgia remain undefined; as result, diagnosis treatment present considerable challenges. On the other hand, endogenous opioid system is believed to regulate intensity emotional responses; hence, it might be expected play key role in enhanced sensitivity experienced patients. One explanation for emergence of disrupted modulation individuals with significant reduction receptor activity or an imbalance levels peptides. Further research essential clarify complex details this abnormality. This complexity arises from notion that improved understanding could contribute development innovative therapeutic strategies aimed at targeting context fibromyalgia. Although progress being made, complete these complexities remains challenge. paradigm has potential revolutionize management fibromyalgia, although its implementation may experience effectiveness approach depends on multiple factors, but implications profound. Despite challenges involved transformation, improving patient care considerable, condition long been inadequately treated.

Язык: Английский

---

MRAP2 Inhibits β-Arrestin-2 Recruitment to the Prokineticin Receptor 2

Current Issues in Molecular Biology, Год журнала: 2024, Номер 46(2), С. 1607 - 1620

Опубликована: Фев. 17, 2024

Melanocortin receptor accessory protein 2 (MRAP2) is a membrane that binds multiple G protein-coupled receptors (GPCRs) involved in the control of energy homeostasis, including prokineticin receptors. These GPCRs are expressed both centrally and peripherally, their endogenous ligands 1 (PK1) (PK2). PKRs couple all G-protein subtypes, such as Gαq/11, Gαs, Gαi, recruit β-arrestins upon PK2 stimulation, although interaction between PKR2 does not trigger internalisation. MRAP2 inhibits anorexigenic effect by binding PKR1 PKR2. The aim this work was to elucidate role modulating PKR2-induced β-arrestin-2 recruitment β-arrestin-mediated signalling. This study could allow identification new specific targets for potential drugs useful treatment various pathologies correlated with prokineticin, particular, obesity.

Язык: Английский

---

Cryo-EM reveals cholesterol binding in the lysosomal GPCR-like protein LYCHOS

Nature Structural & Molecular Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 17, 2025

Язык: Английский

---

GPCR drug discovery: new agents, targets and indications

Nature Reviews Drug Discovery, Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

Язык: Английский

---

Prospects of compounds of herbal plants as anticancer agents: a comprehensive review from molecular pathways

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Июль 22, 2024

Cancer refers to the proliferation and multiplication of aberrant cells inside human body, characterized by their capacity proliferate infiltrate various anatomical regions. Numerous biochemical pathways signaling molecules have an impact on cancer auto biogenesis process. The regulation crucial cellular processes necessary for cell survival proliferation, which are triggered phytochemicals, is significantly influenced pathways. These or components regulated phytochemicals. Medicinal plants a significant reservoir diverse anticancer medications employed in chemotherapy. effects phytochemicals mediated several methods, including induction apoptosis, cessation cycle, inhibition kinases, prevention carcinogenic substances. This paper analyzes phytochemistry seven prominent plant constituents, namely, alkaloids, tannins, flavonoids, phenols, steroids, terpenoids, saponins, focusing involvement MAPK/ERK pathway, TNF signaling, death receptors, p53, p38, actin dynamics. Hence, this review has examined range encompassing structural characteristics potential mechanisms. It underscored significance plant-derived bioactive compounds cancer, utilizing molecular In addition, endeavor also seeks incentivize scientists carry out clinical trials derived from plants.

Язык: Английский

---

Structure-based identification of a G protein–biased allosteric modulator of cannabinoid receptor CB1

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(24)

Опубликована: Июнь 3, 2024

Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site CB1, activating both Gi β-arrestin signaling pathways. activation diverse pathways could result on-target side effects cannabis addiction, which may hinder potential. A significant challenge pharmacology design a ligand that can modulate specific CB1. By leveraging insights from structure–function selectivity relationship (SFSR), we have identified signaling–biased agonist-allosteric modulators (ago-BAMs). Further, two cryoelectron microscopy (cryo-EM) structures reveal binding mode ago-BAM at extrahelical allosteric Combining mutagenesis pharmacological studies, elucidated detailed mechanism ago-BAM-mediated biased signaling. Notably, CB-05 demonstrated analgesic efficacy with fewer effects, minimal drug toxicity no addiction mouse models. In summary, our finding not only suggests ago-BAMs CB1 provide potential nonopioid strategy management but also sheds light on BAM identification GPCRs.

Язык: Английский

---

LIPIDS MODULATE THE DYNAMICS OF GPCR:β-ARRESTIN INTERACTION

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 17, 2024

Abstract β-arrestins are key privileged molecular partners of G-Protein Coupled Receptors (GPCRs), triggering not only their desensitization but also intracellular signaling. Existing structures point to a high conformational plasticity β-arrestin:GPCRs interaction, with two completely different orientations between receptor and β-arrestin. The same set indicates that the C-edge loop β-arrestin could contribute its anchoring membrane, through an interaction specific lipids, namely PI(4,5)P2. Combining dynamics simulations fluorescence spectroscopy, we show 1 interacts membranes even in absence receptor, is enhanced by PI(4,5)P2 presumably holding into lipid bilayer. This helps adopt “receptor ready” orientation. As consequence, favors coupling ghrelin (GHSR). In addition, can known extreme when complexed GHSR. Of importance, shifts equilibrium arrangements, favoring one them. Simulations performed on GHSR:β-arrestin complex suggest release required for these transitions occur distribution around depending orientation receptor-bound arrestin. Taken together, our results highlight how plays true third player role preparing further receptors modulating once protein:protein formed.

Язык: Английский

---

Unveiling G-Protein-Coupled Receptor Conformational Dynamics via Metadynamics Simulations and Markov State Models

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 24, 2025

ABSTRACT The dynamic character of G-protein-coupled receptors (GPCRs) is essential in their functionality as signal transducers. However, the molecular details how ligands affect this conformational repertoire to steer intracellular signaling pathways remain elusive. Here, we address question by modeling landscape growth hormone secretagogue receptor (GHSR-1a), a prototypical peptide-activated class A GPCR, its apo state and bound pharmacologically distinct ligands. We present generally applicable protocol efficiently explore space GHSR-1a that sensitive ligand. Combining metadynamics simulations Markov modeling, computed free energy an agonist, antagonist, or inverse respectively. Consistent with current multi-state model GPCR activity, found populates multiple metastable states whose energies transition probabilities change depending on Furthermore, our models (MSM) have revealed two intermediate not yet been described experimental structures which assume facilitate binding extracellular protein partners, Lastly, MSMs allowed us shed light differences between basal agonistinduced activation. Our results are only compatible previously reported data, but they capture equilibria governing activation unprecedented detail. Due applicability all GPCRs, valuable tool for development pharmaceuticals targeting family.

Язык: Английский

---

AiGPro: a multi-tasks model for profiling of GPCRs for agonist and antagonist

Journal of Cheminformatics, Год журнала: 2025, Номер 17(1)

Опубликована: Янв. 29, 2025

G protein-coupled receptors (GPCRs) play vital roles in various physiological processes, making them attractive drug discovery targets. Meanwhile, deep learning techniques have revolutionized by facilitating efficient tools for expediting the identification and optimization of ligands. However, existing models GPCRs often focus on single-target or a small subset employ binary classification, constraining their applicability high throughput virtual screening. To address these issues, we introduce AiGPro, novel multitask model designed to predict molecule agonists (EC50) antagonists (IC50) across 231 human GPCRs, it first-in-class solution large-scale GPCR profiling. Leveraging multi-scale context aggregation bidirectional multi-head cross-attention mechanisms, our approach demonstrates that ensemble may not be necessary predicting complex states interactions. Through extensive validation using stratified tenfold cross-validation, AiGPro achieves robust performance with Pearson's correlation coefficient 0.91, indicating broad generalizability. This breakthrough sets new standard studies, outperforming previous studies. Moreover, multi-tasking can agonist antagonist activities wide range offering comprehensive perspective ligand bioactivity within this diverse superfamily. facilitate easy accessibility, deployed web-based platform access at https://aicadd.ssu.ac.kr/AiGPro . Scientific Contribution We learning-based multi-task generalize prediction accurately. The is implemented user-friendly web server rapid screening small-molecule libraries, GPCR-targeted discovery. Covering set targets, delivers robust, scalable advancing GPCR-focused therapeutic development. proposed framework incorporates an innovative dual-label strategy, enabling simultaneous classification molecules as agonists, antagonists, both. Each further accompanied confidence score, quantitative measure activity likelihood. advancement moves beyond conventional focusing solely binding affinity, providing more understanding ligand-receptor At core lies Bi-Directional Multi-Head Cross-Attention (BMCA) module, architecture captures forward backward contextual embeddings protein features. By leveraging BMCA, effectively integrates structural sequence-level information, ensuring precise representation molecular Results show highly accurate affinity predictions consistent families. unifying into single architecture, bridge critical gap modeling. enhances accuracy accelerates workflows, valuable

Язык: Английский

---

Advances in cannabinoid receptors pharmacology: from receptor structural insights to ligand discovery

Acta Pharmacologica Sinica, Год журнала: 2025, Номер unknown

Опубликована: Фев. 5, 2025

Язык: Английский

---