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

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

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Computational Elucidation of a Monobody Targeting the Phosphatase Domain of SHP2

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 217 - 217

Published: Feb. 2, 2025

Src homology 2 (SH2) domain-containing phosphatase (SHP2) is a key regulator in cellular signaling pathways because its dysregulation has been implicated various pathological conditions, including cancers and developmental disorders. Despite importance, the molecular basis of SHP2’s regulatory mechanism remains poorly understood, hindering development effective targeted therapies. In this study, we utilized high-specificity monobody Mb11 to investigate interaction with SHP2 domain (PTP) using multiple replica dynamics simulations. Our analyses elucidate precise mechanisms through which achieves selective recognition stabilization SHP2-PTP domain, identifying residues networks essential for high binding specificity dynamics. Furthermore, study highlights pivotal role residue C459 preserving structural integrity functional coherence complex, acting as central node within network underpinning stability efficiency. These findings have significantly advanced understanding underlying involvement disease-related pathology while simultaneously paving way rational design inhibitors, offering significant implications therapeutic strategies SHP2-associated diseases contributing broader scope precision medicine.

Language: Английский

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Probing the role of zinc ion in metallo-β-lactamase inhibitor binding by using multiple molecular dynamics simulations

Results in Chemistry, Journal Year: 2025, Volume and Issue: 15, P. 102171 - 102171

Published: March 6, 2025

Language: Английский

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In silico identification and experimental validation of long-range allosteric inhibition of Staphylococcus aureus Cas9 catalytic activity by an anti-CRISPR protein AcrIIA14

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 143324 - 143324

Published: April 1, 2025

Language: Английский

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Mechanistic Insights into the Mechanism of Allosteric Inhibition of Ubiquitin-Specific Protease 7 (USP7)

Biomolecules, Journal Year: 2025, Volume and Issue: 15(6), P. 749 - 749

Published: May 22, 2025

Ubiquitin-specific protease 7 (USP7), a deubiquitinase enzyme responsible for removing ubiquitin (Ub) from target proteins, plays crucial role in oncogenic pathways and has been implicated various human diseases. X-ray crystallography revealed distinct conformations of USP7, including apo (ligand-free), allosteric inhibitor-, Ub-bound states. However, the dynamic mechanisms underlying inhibition USP7 remain unclear. This study investigates effect inhibitor binding on dynamics through multiple replica molecular simulations. Our results demonstrate that Ub stabilizes conformation, while increases flexibility variability fingers palm domains USP7. Furthermore, our analysis local regions reveals not only restrains C-terminal site, thereby impeding accessibility to but also disrupts proper alignment catalytic triad (Cys223-His464-Asp481) Additionally, community network indicates intra-domain communications within domain are significantly enhanced upon binding. an induces shift enzyme’s conformational equilibrium, effectively disrupting its activity modulation.

Language: Английский

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Computational revealing Infigratinib resistance to the FGFR2 N549H and N549K mutations

Journal of Experimental Nanoscience, Journal Year: 2024, Volume and Issue: 20(1)

Published: Dec. 17, 2024

Fibroblast growth factor receptor 2 (FGFR2) is a tyrosine kinase that involved in many human cancers such as intrahepatic cholangiocarcinomas and hepatocellular carcinomas. The clinically acquired FGFR2 N549H/K mutations make the treatment of Infigratinib ineffective. Here, molecular docking, multiple-replica dynamics (MD) simulations, binding free energy calculations were used to reveal mechanism resistance mutants. MD simulations indicated both disrupt local hydrogen bonds or salt bridges formed by His544, Asn549, Glu565, Lys641. Binding calculation results suggested decrease van der Waals interactions electrostatic interaction are responsible for weakening affinity Residue-based decomposition analysis further showed with key residues Leu487, Ala567, Gly570, Leu633 become significantly weaker mutants compared wild-type kinase. We anticipate our will provide useful guide design potential inhibitors against

Language: Английский

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