Pharmacologically targeting intracellular allosteric sites of GPCRs for drug discovery

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(12), P. 103803 - 103803

Published: Oct. 17, 2023

Language: Английский

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Allostery

Quarterly Reviews of Biophysics, Journal Year: 2025, Volume and Issue: 58

Published: Jan. 1, 2025

Abstract Allostery describes the ability of biological macromolecules to transmit signals spatially through molecule from an allosteric site – a that is distinct orthosteric binding sites primary, endogenous ligands functional or active site. This review starts with historical overview and description classical example allostery hemoglobin other well-known examples (aspartate transcarbamoylase, Lac repressor, kinases, G-protein-coupled receptors, adenosine triphosphate synthase, chaperonin). We then discuss fringe allostery, including intrinsically disordered proteins inter-enzyme influence dynamics, entropy, conformational ensembles landscapes on mechanisms, capture essence field. Thereafter, we give over central methods for investigating molecular covering experimental techniques as well simulations artificial intelligence (AI)-based methods. conclude allostery-based drug discovery, its challenges opportunities: recent advent AI-based methods, compounds are set revolutionize discovery medical treatments.

Language: Английский

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Molecular dynamics simulations: Insights into protein and protein ligand interactions

Advances in pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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The Evolving Landscape of Protein Allostery: From Computational and Experimental Perspectives

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169060 - 169060

Published: March 1, 2025

Language: Английский

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Conformational mapping of GPCR activation: dynamic allosteric site discovery in V2R through MD-MSM and mutual information analysis

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: May 2, 2025

Allostery governs‌ the functional dynamics of proteins by regulating their conformational transitions. ‌The development allosteric modulators has emerged as a promising therapeutic strategy‌, leveraging superior target specificity ‌and reduced off-target effects compared to orthosteric compounds‌. ‌A critical barrier in this field remains‌ identification dynamic sites, ‌which are often undetectable conventional structural analyses due transient nature‌. ‌To address challenge,‌ we established ‌an integrative computational framework‌ combining molecular (MD), Markov state modeling (MSM), and mutual information (MI) analysis ‌to probe‌ sites ‌in class A G protein-coupled receptor (GPCR) prototype, vasopressin V2 (V2R)‌. ‌Through‌ multi-replica MD simulations, ‌we reconstructed‌ receptor's landscape, was statistically refined‌ via MSM resolve‌ equilibrium populations transition kinetics‌. ‌Key mechanistic features‌ activation-related motifs ‌were quantitatively characterized‌. ‌Candidate were systematically ranked‌ through MI-driven residue interaction network analysis, ‌prioritizing‌ pharmacologically targetable regions. ‌This strategy revealed‌ novel site ‌on V2R intracellular interface‌, ‌whose relevance confirmed through‌ structure-guided mutagenesis ‌and‌ BRET-based signaling assays. ‌Our findings‌ not only ‌elucidate activation mechanism at atomic resolution‌ but also ‌establish conformation-aware platform‌ for ‌rational discovery binding pockets‌, ‌providing transformative approach for‌ GPCR-targeted drug discovery.

Language: Английский

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Designing drugs and chemical probes with the dualsteric approach

Chemical Society Reviews, Journal Year: 2023, Volume and Issue: 52(24), P. 8651 - 8677

Published: Jan. 1, 2023

Dualsteric modulators are praised for a balance of potency and selectivity, overcoming drug resistance, function bias, an easy scheme partial agonist. It could also be used to design fluorescent tracers study protein conformations.

Language: Английский

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Machine learning approaches in predicting allosteric sites

Published: Jan. 17, 2024

Allosteric regulation is a fundamental biological mechanism that can control critical cellular processes via allosteric modulator binding to protein distal functional sites. The advantages of modulators over orthosteric ones have sparked the development numerous computational approaches, such as identification sites, facilitate drug discovery. Building on success Machine Learning (ML) models for solving complex problems in biology and chemistry, several ML predicting sites been developed. In this review, we provide an overview these discuss future perspectives powered by field Artificial Intelligence Language Models.

Language: Английский

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Decoupling the dynamic mechanism revealed by FGFR2 mutation-induced population shift

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: 42(4), P. 1940 - 1951

Published: May 31, 2023

The fibroblast growth factor receptor 2 (FGFR2) is a key component in cellular signaling networks, and its dysfunctional activation has been implicated various diseases including cancer developmental disorders. Mutations at the loop (A-loop) have suggested to trigger an increased basal kinase activity. However, molecular mechanism underlying this highly dynamic process not fully understood due limitation of static structural information. Here, we conducted multiple, large-scale Gaussian accelerated dynamics simulations five (K659E, K659N, K659M, K659Q, K659T) FGFR2 mutants A-loop, comprehensively analyzed basis activation. results quantified population shift each system, revealing that all had higher proportion active-like states. Using Markov state models, extracted representative structure different conformational states identified residues related Furthermore, community network analysis showed enhanced information connections mutants, highlighting long-range allosteric communication between A-loop hinge region. Our findings may provide insights into for drug discovery.Communicated by Ramaswamy H. Sarma

Language: Английский

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Designed dualsteric modulators: A novel route for drug discovery

Drug Discovery Today, Journal Year: 2024, Volume and Issue: 29(10), P. 104141 - 104141

Published: Aug. 19, 2024

Language: Английский

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Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase

Frontiers in Molecular Biosciences, Journal Year: 2022, Volume and Issue: 9

Published: Dec. 19, 2022

Calcium (Ca2+) signaling plays an important role in the regulation of many cellular functions. Ca2+-binding protein calmodulin (CaM) serves as a primary effector calcium function. Ca2+/CaM binds to death-associated kinase 1 (DAPK1) regulate intracellular pathways. However, mechanism underlying influence Ca2+ on conformational dynamics DAPK1-CaM interactions is still unclear. Here, we performed large-scale molecular (MD) simulations complex Ca2+-bound and-unbound states reveal importance Ca2+. MD revealed that removal increased anti-correlated inter-domain motions between DAPK1 and CaM, which weakened interactions. Binding free energy calculations validated decreased Ca2+-unbound state. Structural analysis further caused significant changes at interface, especially helices α1, α2, α4, α6, α7 from CaM basic loop phosphate-binding DAPK1. These results may be useful understand biological physiological processes.

Language: Английский

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