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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Negative allosteric modulation of the glucagon receptor by RAMP2

Cell, Journal Year: 2023, Volume and Issue: 186(7), P. 1465 - 1477.e18

Published: March 1, 2023

Language: Английский

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Roles of Accelerated Molecular Dynamics Simulations in Predictions of Binding Kinetic Parameters

Mini-Reviews in Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 24(14), P. 1323 - 1333

Published: Jan. 24, 2024

Rational predictions on binding kinetics parameters of drugs to targets play significant roles in future drug designs. Full conformational samplings are requisite for accurate kinetic parameters. In this review, we mainly focus the applications enhanced sampling technologies calculations and residence time drugs. The methods involved molecular dynamics simulations applied not only probe changes but also reveal that is efficiency. For special attention paid accelerated (aMD) Gaussian aMD (GaMD) have been adopted predict association or disassociation rate constant. We expect review can provide useful information design.

Language: Английский

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New Insights into the Structure and Function of Class B1 GPCRs

Endocrine Reviews, Journal Year: 2022, Volume and Issue: 44(3), P. 492 - 517

Published: Dec. 22, 2022

Abstract G protein–coupled receptors (GPCRs) are the largest family of cell surface receptors. Class B1 GPCRs constitute a subfamily 15 that characteristically contain large extracellular domains (ECDs) and respond to long polypeptide hormones. critical regulators homeostasis, and, as such, many important drug targets. While most transmembrane proteins, including GPCRs, recalcitrant crystallization, recent advances in cryo-electron microscopy (cryo-EM) have facilitated rapid expansion structural understanding membrane proteins. As testament this success, structures for all class bound proteins been determined by cryo-EM past 5 years. Further uncovered dynamics these receptors, ligands, signaling partners. Here, we examine underpinnings with an emphasis on structure–function relationships.

Language: Английский

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Probing mutation-induced conformational transformation of the GTP/M-RAS complex through Gaussian accelerated molecular dynamics simulations

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 38(1)

Published: April 14, 2023

Mutations highly affect the structural flexibility of two switch domains in M-RAS considered an important target anticancer drug design. Gaussian accelerated molecular dynamics (GaMD) simulations were applied to probe effect mutations P40D, D41E, and P40D/D41E/L51R on conformational transition from GTP-bound M-RAS. The analyses free energy landscapes (FELs) not only reveal that three induce less energetic states than wild-type (WT) but also verify are extremely disordered. Principal component analysis (PCA) suggest greatly collective motions mostly overlap with binding regions its effectors, which turn disturbs activity interaction network between GTP show high instability hydrogen bonding interactions (HBIs) residue 41 Y42 domain I drives disordered domains. This work is expected provide a mechanism for deeply understanding function future design towards treatment cancers.

Language: Английский

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Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 30, 2024

Two-thirds of signaling hormones and one-third approved drugs exert their effects by binding modulating the G protein-coupled receptors (GPCRs) activation. While activation mechanism for monomeric GPCRs has been well-established, little is known about in dimeric form. Here, combining transition pathway generation, extensive atomistic simulation-based Markov state models, experimental assays, we reveal an asymmetric, stepwise millisecond allosteric metabotropic glutamate receptor subtype 5 (mGlu5), obligate class C GPCR. The dynamic picture presented that agonist induces ectodomains compaction, amplified precise association cysteine-rich domains, ultimately loosely bringing intracellular 7-transmembrane (7TM) domains into proximity establishing asymmetric TM6-TM6 interface. active inter-domain interface enhances intra-domain flexibility, triggering micro-switches crucial downstream signal transduction. Furthermore, show positive modulator stabilizes both 7TM open, extended ICL2 conformation. This stabilization leads to formation a pseudo-cavity composed ICL2, ICL3, TM3, C-terminus, which facilitates protein coordination. Our strategy may be generalizable characterizing events other systems. Activation form remains enigmatic. authors present characterization mGlu5, GPCR, suggesting mechanism.

Language: Английский

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Computational elucidation of allosteric communication in proteins for allosteric drug design

Drug Discovery Today, Journal Year: 2022, Volume and Issue: 27(8), P. 2226 - 2234

Published: March 18, 2022

Language: Английский

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Markov State Models and Molecular Dynamics Simulations Reveal the Conformational Transition of the Intrinsically Disordered Hypervariable Region of K-Ras4B to the Ordered Conformation

Journal of Chemical Information and Modeling, Journal Year: 2022, Volume and Issue: 62(17), P. 4222 - 4231

Published: Aug. 22, 2022

K-Ras4B, the most frequently mutated Ras isoform in human tumors, plays a vital part cell growth, differentiation, and survival. Its tail, C-terminal hypervariable region (HVR), is involved anchoring K-Ras4B at cellular plasma membrane isoform-specific protein–protein interactions signaling. In inactive guanosine diphosphate-bound state, intrinsically disordered HVR interacts with catalytic domain effector-binding region, rendering its autoinhibited state. Activation releases from domain, ensemble favoring an ordered α-helical structure. The large-scale conformational transition of to conformation remains poorly understood. Here, we deploy computational scheme that integrates path-generation algorithm, extensive molecular dynamics simulation, Markov state model analysis investigate landscape pathway. Our findings reveal stepwise pathway for uncover several key substates along Importantly, between are unraveled, highlighting pathogenesis mild mutations congenital developmental anomaly syndromes. Together, these provide deeper understanding mechanism regulation activity atomic level.

Language: Английский

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Binding modes of GDP, GTP and GNP to NRAS deciphered by using Gaussian accelerated molecular dynamics simulations

SAR and QSAR in environmental research, Journal Year: 2023, Volume and Issue: 34(1), P. 65 - 89

Published: Jan. 2, 2023

Probing binding modes of GDP, GTP and GNP to NRAS are significance for understanding the regulation mechanism on activity RAS proteins. Four separate Gaussian accelerated molecular dynamics (GaMD) simulations were performed apo, GDP-, GTP- GNP-bound NRAS. Dynamics analyses suggest that three ligands highly affects conformational states switch domains from NRAS, which disturbs its effectors. The free energy landscapes (FELs) indicate induces more energetic compared apo but presence makes ordered than GDP GNP. information interaction networks with reveals π-π residue F28 salt bridge interactions K16 D119 stabilize Meanwhile magnesium ion plays a role in is favourable associations This work expected provide useful deeply function

Language: Английский

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Unraveling the Interplay of Extracellular Domain Conformational Changes and Parathyroid Hormone Type 1 Receptor Activation in Class B1 G Protein-Coupled Receptors: Integrating Enhanced Sampling Molecular Dynamics Simulations and Markov State Models

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(4), P. 844 - 853

Published: Feb. 5, 2024

Parathyroid hormone (PTH) type 1 receptor (PTH1R), as a typical class B1 G protein-coupled (GPCR), is responsible for regulating bone turnover and maintaining calcium homeostasis, its dysregulation has been implicated in the development of several diseases. The extracellular domain (ECD) PTH1R crucial recognition binding ligands, may exhibit an autoinhibited state with closure ECD absence ligands. However, correlation between conformations activation remains unclear. Thus, this study combines enhanced sampling molecular dynamics (MD) simulations Markov models (MSMs) to reveal possible relevance PTH1R. First, 22 intermediate structures are generated from active conducted 10 independent 200 ns each. Then, MSM constructed based on cumulative 44 μs six identified microstates. Finally, potential interplay conformational changes well cryptic allosteric pockets states during revealed. Overall, our findings that specific provide essential insights GPCR biology developing novel modulators targeting sites.

Language: Английский

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