Free Energy, Rates, and Mechanism of Transmembrane Dimerization in Lipid Bilayers from Dynamically Unbiased Molecular Dynamics Simulations DOI Creative Commons

Emil Jackel,

Gianmarco Lazzeri, Roberto Covino

et al.

The Journal of Physical Chemistry B, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 23, 2025

The assembly of proteins in membranes plays a key role many crucial cellular pathways. Despite their importance, characterizing transmembrane remains challenging for experiments and simulations. Equilibrium molecular dynamics simulations do not cover the time scales required to sample typical assembly. Hence, most studies rely on enhanced sampling schemes that steer along collective variable should encode all slow degrees freedom. However, given complexity condensed-phase lipid environment, this is far from trivial, with consequence free energy profiles dimerization can be poorly converged. Here, we introduce an alternative approach, which relies only simulating short, dynamically unbiased paths, avoiding using variables or biasing forces. By merging obtain profiles, rates, mechanisms same set We showcase our algorithm by spontaneous association dissociation protein bilayer, popular coarse-grained Martini force field. Our represents promising way investigate processes biologically relevant membranes, overcoming some challenges conventional methods.

Language: Английский

GPCR drug discovery: new agents, targets and indications DOI
José A. Lorente, Aleksandr V. Sokolov, Gavin Ferguson

et al.

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Language: Английский

Citations

2
Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery DOI Creative Commons

Xin Qiao,

Xiaolong Li, Mingyang Zhang

et al.

Pharmacological Research, Journal Year: 2025, Volume and Issue: 212, P. 107574 - 107574

Published: Jan. 2, 2025

G protein-coupled receptors (GPCRs) represent the largest family of membrane and are highly effective targets for therapeutic drugs. GPCRs couple different downstream effectors, including proteins (such as Gi/o, Gs, G12, Gq) β-arrestins β-arrestin 1 2) to mediate diverse cellular physiological responses. Biased signaling allows specific activation certain pathways from full range receptors' capabilities. Targeting more variable allosteric sites, which spatially conserved orthosteric represents a novel approach in biased GPCR drug discovery, leading innovative strategies targeting GPCRs. Notably, emergence cryptic sites on has expanded repertoire available improved receptor subtype selectivity. Here, we conduct summary recent progress structural determination elucidate mechanisms induced by modulators. Additionally, discuss means identify design modulators based through structure-based design, is an advanced pharmacotherapeutic treating GPCR-associated diseases.

Language: Английский

Citations

1
Research article for 1st revision to the Chemico-Biological InteractionModulatory roles of capsaicin on thermogenesis in C2C12 myoblasts and the skeletal muscle of mice DOI

Alfin Mohammad Abdillah,

Jae Young Lee,

Young Rok Lee

et al.

Chemico-Biological Interactions, Journal Year: 2025, Volume and Issue: unknown, P. 111380 - 111380

Published: Jan. 1, 2025

Language: Английский

Citations

1
Precision Psychobiotics for Gut–Brain Axis Health: Advancing the Discovery Pipelines to Deliver Mechanistic Pathways and Proven Health Efficacy DOI Creative Commons
Rebecca F. Slykerman, Naomi Davies, Klára Vlčková

et al.

Microbial Biotechnology, Journal Year: 2025, Volume and Issue: 18(1)

Published: Jan. 1, 2025

ABSTRACT Advancing microbiome–gut–brain axis science requires systematic, rational and translational approaches to bridge the critical knowledge gaps currently preventing full exploitation of gut microbiome as a tractable therapeutic target for gastrointestinal, mental brain health. Current research is still marked by many open questions that undermine widespread application humans. For example, lack mechanistic understanding probiotic effects means it remains unclear why even apparently closely related strains exhibit different in vivo. live microbial psychobiotics, consensus on their adjunct treatments conventional neuromodulators, use unmedicated populations or at‐risk cohorts with sub‐clinical symptomatology warranted. This missing information both sides equation when treating central nervous system (CNS) conditions makes psychobiotic challenging, especially compared other pharmaceutical functional food approaches. Expediting transition from positive preclinical data proven benefits humans includes interpreting promises pitfalls animal behavioural assays, well navigating mechanism‐informed decision making select right microbe(s) job. In this review, we consider how these decisions can be supported light accrued range clinical studies across healthy, pathological study populations, where specific have been evaluated context gastrointestinal physiology, function behaviour. Examples successful, partial unsuccessful translation bench bedside are considered. We also discuss developments silico analyses enhanced our moved towards pinpointing host–microbe interactions most important optimal gut–brain function. Combining assays vitro ex vivo domains incorporating model organisms prime discovery pipelines promising rationally selected candidates.

Language: Английский

Citations

1
Cannabinoid receptor 1 ligands: Biased signaling mechanisms driving functionally selective drug discovery DOI
Lei Tian,

Taotao Qiang,

Shanglong Liu

et al.

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108795 - 108795

Published: Jan. 1, 2025

Language: Английский

Citations

1
Raptin, a sleep-induced hypothalamic hormone, suppresses appetite and obesity DOI Creative Commons

Ling‐Qi Xie,

Biao Hu,

Ren-Bin Lu

et al.

Cell Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 29, 2025

Abstract Sleep deficiency is associated with obesity, but the mechanisms underlying this connection remain unclear. Here, we identify a sleep-inducible hypothalamic protein hormone in humans and mice that suppresses obesity. This cleaved from reticulocalbin-2 (RCN2), name it Raptin. Raptin release timed by circuit vasopressin-expressing neurons suprachiasmatic nucleus to RCN2-positive paraventricular nucleus. levels peak during sleep, which blunted sleep deficiency. binds glutamate metabotropic receptor 3 (GRM3) of hypothalamus stomach inhibit appetite gastric emptying, respectively. Raptin-GRM3 signaling mediates anorexigenic effects via PI3K-AKT signaling. Of note, verify connections between deficiencies sleeping state, impaired release, obesity patients Moreover, carrying an RCN2 nonsense variant present night eating syndrome These data define unique food intake prevents

Language: Английский

Citations

1
Direct effect of membrane environment on the activation of mGluR2 revealed by single-molecule FRET DOI
Chiranjib Banerjee, Brandon Wey-Hung Liauw, Reza Vafabakhsh

et al.

Structure, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

1
De novodesign of miniprotein agonists and antagonists targeting G protein-coupled receptors DOI Creative Commons
Edin Muratspahić,

David Feldman,

David E. Kim

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 23, 2025

Abstract G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery development, yet the design of protein agonists antagonists has been challenging as GPCRs integral membrane proteins conformationally dynamic. Here we describe computational de novo methods a high throughput “receptor diversion” microscopy based screen generating GPCR binding miniproteins with affinity, potency selectivity, use these to generate MRGPRX1 CXCR4, GLP1R, GIPR, GCGR CGRPR antagonists. Cryo-electron data reveals atomic-level agreement between designed experimentally determined structures CGRPR-bound MRGPRX1-bound agonists, confirming precise conformational control receptor function. Our screening approach opens new frontiers development.

Language: Английский

Citations

1
Genome-wide pan-GPCR cell libraries accelerate drug discovery DOI Creative Commons
Hanting Yang, Yongfu Wang, Wei Liu

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(10), P. 4296 - 4311

Published: June 26, 2024

G protein-coupled receptors (GPCRs) are pivotal in mediating diverse physiological and pathological processes, rendering them promising targets for drug discovery. GPCRs account about 40% of FDA-approved drugs, representing the most successful targets. However, only approximately 15% 800 human targeted by market leaving numerous opportunities discovery among remaining receptors. Cell expression systems play crucial roles GPCR field, including novel target identification, structural functional characterization, potential ligand screening, signal pathway elucidation, safety evaluation. Here, we discuss principles, applications, limitations widely used cell GPCR-targeted discovery, function investigation, pharmacological property studies. We also propose three strategies constructing genome-wide pan-GPCR libraries, which will provide a powerful platform facilitate study mechanisms evaluation, ultimately accelerating process

Language: Английский

Citations

7
Neutrophil diversity and function in health and disease DOI Creative Commons

F Zhang,

Yidan Xia,

Jiayang Su

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Dec. 5, 2024

Abstract Neutrophils, the most abundant type of granulocyte, are widely recognized as one pivotal contributors to acute inflammatory response. Initially, neutrophils were considered mobile infantry innate immune system, tasked with immediate response invading pathogens. However, recent studies have demonstrated that versatile cells, capable regulating various biological processes and impacting both human health disease. Cytokines other active mediators regulate functional activity by activating multiple receptors on these thereby initiating downstream signal transduction pathways. Dysfunctions in disruptions neutrophil homeostasis been implicated pathogenesis numerous diseases, including cancer disorders, often due aberrant intracellular signaling. This review provides a comprehensive synthesis functions, integrating advancements this field. Moreover, it examines roles signaling pathways involved regulation activity. The pathophysiology diseases emerging therapeutic approaches targeting them also elaborated. addresses current limitations within field research, highlighting critical gaps knowledge warrant further investigation. In summary, seeks establish multidimensional model regulation, providing new perspectives for potential clinical applications research.

Language: Английский

Citations

6