Exploring the taste presentation and receptor perception mechanism of salty peptides from Stropharia rugosoannulata based on molecular dynamics and thermodynamics simulation DOI Creative Commons
Wen Li,

Shuai Sun,

Wanchao Chen

et al.

Deleted Journal, Journal Year: 2023, Volume and Issue: 13(4), P. 2277 - 2288

Published: Sept. 26, 2023

The taste presentation and receptor perception mechanism of the salty peptide Stropharia rugosoannulata were predicted verified using omics molecular interaction techniques. combination aspartic acid (D) glutamic (E), or fragments composed arginine (R), constitute characteristic structural basis peptides S. rugosoannulata. intensity positively correlates with its concentration within a specific range ((0.25-1.0) mg/mL). more easily recognizes first amino residue at N-terminal in peptides. GLU513, ASP707, VAL508 are critical residues for to recognize TRPV1 is specifically recognizing Hydrogen bonds electrostatic interactions main driving forces between receptors. KSWDDFFTR has most potent binding capacity tremendous potential application sodium salt substitution. This study confirmed that peptides, analyzed receptor-peptide interaction, provided new idea understanding

Language: Английский

Comparative Study of Allosteric GPCR Binding Sites and Their Ligandability Potential DOI Creative Commons
S. Reinach Peter, Lydia Siragusa,

Morgan Thomas

et al.

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(21), P. 8176 - 8192

Published: Oct. 23, 2024

The steadily growing number of experimental G-protein-coupled receptor (GPCR) structures has revealed diverse locations allosteric modulation, and yet few drugs target them. This gap highlights the need for a deeper understanding modulation in GPCR drug discovery. current work introduces systematic annotation scheme to structurally classify binding sites based on class, transmembrane helix contacts, and, membrane-facing sites, membrane sublocation. specific was applied 107 bound by small molecules contributing 24 distinct comparative evaluation three site detection methods (BioGPS, SiteMap, FTMap). BioGPS identified most 22 sites. In addition, our property analysis showed that extrahelical ligands represent chemical space characterized shallow pockets with low volume, corresponding an enrichment halogens. Furthermore, we demonstrated combining ligand similarity can be viable method ligandability assessment. One challenge regarding prediction is shaping effect observed site, especially where ligand-induced pronounced. To knowledge, this first study presenting standardized GPCRs, it allows comparison across different receptors objective way. insight from provides framework future studies potential targeting development.

Language: Английский

Citations

4
Novel Orthosteric/Allosteric Ligands of Cannabinoid Receptors: An Unexpected Pharmacological Profile DOI
Rebecca Ferrisi, Beatrice Polini,

Anna Maria Smolyakova

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

The design of dualsteric/bitopic receptor ligands as compounds capable simultaneously interacting with both the orthosteric and an allosteric binding site has gained importance to achieve enhanced specificity minimize off-target effects. In this work, we reported synthesis biological evaluation a new series compounds, namely,

Language: Английский

Citations

0
INFLUENCE OF DIFFERENT TYPES OF ALLOSTERIC REGULATORS ON THE BASAL AND HORMONE-STIMULATED ACTIVITY OF THE THYROID-STIMULATED HORMONE RECEPTOR IN VITRO AND IN VIVO DOI
К. В. Деркач, Е. А. Шпакова, E. A. Didenko

et al.

Reviews on Clinical Pharmacology and Drug Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Background: Antithyroid drugs used to treat autoimmune hyperthyroidism lead thyroid hormone deficiency when for a long time. In this regard, it is relevant develop thyroid-stimulating receptor (TSHR) regulators capable of inhibiting TSHR activation by agonists acting on the orthosteric site (TSH, autoantibodies TSHR) and stimulating its basal activity. This function can be performed allosteric with agonist activity negative modulators (ago-NAM).Aim: A comparative study effects TPY4, thieno[2,3-d]-pyrimidine derivative, peptide 612–627-Lys(Palm)Ala, derivative third cytoplasmic loop TSHR, TSH-stimulated adenylate cyclase (AC) in membranes thyrotropin-releasing (TRH)-stimulated levels administered male rats.Materials methods: The AC isolated from rat gland was measured radioisotope method using [α-32P]-ATP as substrate. ability affect TRH-stimulated hormones assessed treating rats 612–627-Lys(Palm)Ala (750 μg/kg) TPY4 (15 mg/kg). concentrations free thyroxine (FT4), total triiodothyronine (TT3), TSH blood were determined enzyme immunoassay.Results: membranes, micromolar increased decreased stimulation (10-9 M), more effective an inhibitor effect, while stimulated greater extent. When rats, both compounds, although varying degrees, production FT4 TT3, but at same time prevented increase upon axis TRH (100 μg/rat). They did not have significant effect level blood, indicates that their targets are localized thyrocytes.Conclusions: Structurally distinct ligands characterized similar spectrum pharmacological activity, functioning ago-NAM TSHR. Their prevent hyperactivation without causing decrease could treatment hyperthyroidism.

Language: Английский

Citations

0
Bioorthogonal Tethering Enhances Drug Fragment Affinity for G Protein-Coupled Receptors in Live Cells DOI Creative Commons
Jordan M. Mattheisen, Chris Limberakis, Roger B. Ruggeri

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(20), P. 11173 - 11184

Published: April 28, 2023

G protein-coupled receptors (GPCRs) modulate diverse cellular signaling pathways and are important drug targets. Despite the availability of high-resolution structures, discovery allosteric modulators remains challenging due to dynamic nature GPCRs in native membranes. We developed a strategy covalently tether fragments adjacent sites enhance their potency enable fragment-based screening cell-based systems. employed genetic code expansion site-specifically introduce noncanonical amino acids with reactive groups C–C chemokine receptor 5 (CCR5) near an binding site for maraviroc. then used molecular dynamics simulations design heterobifunctional maraviroc analogues consisting fragment connected by flexible linker moiety capable undergoing bioorthogonal coupling reaction. synthesized library these inverse electron demand Diels–Alder reaction couple engineered CCR5 live cells, which were assayed using assays. Tetherable low-affinity displayed increase unnatural that site. The we describe novel should prove useful probe or cryptic functionality GPCR-targeted discovery.

Language: Английский

Citations

10
Exploring the taste presentation and receptor perception mechanism of salty peptides from Stropharia rugosoannulata based on molecular dynamics and thermodynamics simulation DOI Creative Commons
Wen Li,

Shuai Sun,

Wanchao Chen

et al.

Deleted Journal, Journal Year: 2023, Volume and Issue: 13(4), P. 2277 - 2288

Published: Sept. 26, 2023

The taste presentation and receptor perception mechanism of the salty peptide Stropharia rugosoannulata were predicted verified using omics molecular interaction techniques. combination aspartic acid (D) glutamic (E), or fragments composed arginine (R), constitute characteristic structural basis peptides S. rugosoannulata. intensity positively correlates with its concentration within a specific range ((0.25-1.0) mg/mL). more easily recognizes first amino residue at N-terminal in peptides. GLU513, ASP707, VAL508 are critical residues for to recognize TRPV1 is specifically recognizing Hydrogen bonds electrostatic interactions main driving forces between receptors. KSWDDFFTR has most potent binding capacity tremendous potential application sodium salt substitution. This study confirmed that peptides, analyzed receptor-peptide interaction, provided new idea understanding

Language: Английский

Citations

10