Recent developments in molecular modeling tools and applications related to pharmaceutical and biomedical research

Journal of Pharmaceutical and Biomedical Analysis, Год журнала: 2023, Номер 238, С. 115836 - 115836

Опубликована: Ноя. 3, 2023

In modern pharmaceutical and biomedical research, molecular modeling represents a useful tool to explore processes their mechanistic bases at the level. Integrating experimental virtual analysis is fruitful approach study ligand-receptor interaction in chemical, biochemical biological environments. these fields, docking dynamics are considered privileged techniques for (bio)macromolecules related complexes. This review aims present current landscape of research by examining selected representative applications published last years highlighting topics trends this field. Thus, systematic compilation all literature has not been attempted herein. After brief overview main theoretical computational tools used investigate mechanisms level, recent drug discovery, ligand binding studying protein conformation function will be discussed. Furthermore, specific sections devoted application unravelling enantioselective underlying enantioseparation chiral compounds interest as well new forms noncovalent interactivity identified The general aim provide reader with topic, advancements outlooks drawbacks pitfalls still affecting applicability methods field research.

Язык: Английский

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Flipping the GPCR Switch: Structure-Based Development of Selective Cannabinoid Receptor 2 Inverse Agonists

ACS Central Science, Год журнала: 2024, Номер 10(5), С. 956 - 968

Опубликована: Март 11, 2024

We report a blueprint for the rational design of G protein coupled receptor (GPCR) ligands with tailored functional response. The present study discloses structure-based cannabinoid type 2 (CB2R) selective inverse agonists (S)-1 and (R)-1, which were derived from privileged agonist HU-308 by introduction phenyl group at gem-dimethylheptyl side chain. Epimer (R)-1 exhibits high affinity CB2R Kd = 39.1 nM serves as platform synthesis wide variety probes. Notably, first time these fluorescent probes retain their functionality, affinity, selectivity independent linker fluorophore substitution. Ligands (S)-1, derivatives act in CB2R-mediated cAMP well recruitment assays do not trigger β-arrestin-receptor association. Furthermore, no activation was detected live cell ERK1/2 phosphorylation Ca2+-release assays. Confocal fluorescence imaging experiments (R)-7 (Alexa488) (R)-9 (Alexa647) employing BV-2 microglial cells visualized expressed endogenous levels. Finally, molecular dynamics simulations corroborate initial docking data restrict movement toggle switch Trp2586.48 thereby stabilize its inactive state.

Язык: Английский

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Selective fluorescent labeling of cellular proteins and its biological applications

Chemical Society Reviews, Год журнала: 2024, Номер 53(19), С. 9446 - 9489

Опубликована: Янв. 1, 2024

Proteins, which are ubiquitous in cells and critical to almost all cellular functions, indispensable for life. Fluorescence imaging of proteins is key understanding their functions within native milieu, as it provides insights into protein localization, dynamics, trafficking living systems. Consequently, the selective labeling target with fluorophores has emerged a highly active research area, encompassing bioorganic chemistry, chemical biology, cell biology. Various methods selectively tissues have been established continually being developed visualize characterize proteins. This review highlights findings reported since 2018, focus on small organic biological applications studying protein-associated events. We also discuss strengths weaknesses each approach utility

Язык: Английский

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Lysine-Reactive N-Acyl-N-aryl Sulfonamide Warheads: Improved Reaction Properties and Application in the Covalent Inhibition of an Ibrutinib-Resistant BTK Mutant

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(48), С. 26202 - 26212

Опубликована: Ноя. 21, 2023

The covalent inhibition of a target protein has gained widespread attention in the field drug discovery. Most current drugs utilize high reactivity cysteines toward modest electrophiles. However, there is growing need for warheads that can lysine residues to expand range covalently druggable proteins and deal with emerging mutations resistant cysteine-targeted drugs. We have recently developed an N-acyl-N-alkyl sulfonamide (NASA) as lysine-targeted electrophile. Despite its successful application, this NASA warhead suffered from instability physiological environments, such serum-containing medium, because intrinsic reactivity. In study, we sought modify structure found N-acyl-N-aryl sulfonamides (ArNASAs) are promising electrophiles use strategy. prepared focused library ArNASA derivatives diverse structures identified several candidates suppressed hydrolysis-mediated inactivation reduced nonspecific reactions off-target proteins, without sacrificing target. These reaction properties enabled improved intracellular heat shock 90 (HSP90) presence serum development first irreversible inhibitor ibrutinib-resistant Bruton's tyrosine kinase (BTK) bearing C481S mutation. This study clearly demonstrated set create highly potent highlighted importance enriching arsenal lysine-reactive warheads.

Язык: Английский

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N-Acyl-N-Alkyl Sulfonamide Probes for Ligand-Directed Covalent Labeling of GPCRs: The Adenosine A_2B Receptor as Case Study

ACS Chemical Biology, Год журнала: 2024, Номер 19(7), С. 1554 - 1562

Опубликована: Июнь 26, 2024

Small molecular tool compounds play an essential role in the study of G protein-coupled receptors (GPCRs). However, most often occupy orthosteric binding site, hampering GPCRs upon ligand binding. To overcome this problem, ligand-directed labeling techniques have been developed that leave a reporter group covalently bound to GPCR, while allowing subsequent ligands bind. In work, we applied such strategy adenosine A

Язык: Английский

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Ligand-Directed Labeling of the Adenosine A₁ Receptor in Living Cells

Journal of Medicinal Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Июль 12, 2024

The study of protein function and dynamics in their native cellular environment is essential for progressing fundamental science. To overcome the requirement genetic modification or limitations dissociable fluorescent ligands, ligand-directed (LD) chemistry has most recently emerged as a complementary, bioorthogonal approach labeling proteins. Here, we describe rational design, development, application first A1AR living cells. We pharmacologically demonstrate covalent expressed cells while orthosteric binding site remains available. probes were imaged using confocal microscopy fluorescence correlation spectroscopy to localization Additionally, allowed visualization specific A1ARs endogenously dorsal root ganglion (DRG) neurons. LD developed here hold promise illuminating ligand-binding, receptor signaling, trafficking more physiologically relevant environments.

Язык: Английский

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A universal cannabinoid CB1 and CB2 receptor TR-FRET kinetic ligand-binding assay

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Апрель 9, 2025

The kinetics of ligand binding to G protein-coupled receptors (GPCRs) is an important optimization parameter in drug discovery. Traditional radioligand assays are labor-intensive, preventing their application at the early stages Fluorescence-based offer several advantages, including a possibility develop homogeneous format, continuous data collection, and higher throughput. This study sought fluorescence-based assay investigate ligand-binding human cannabinoid type 1 2 (CB1R CB2R). We synthesized D77, novel tracer derived from non-selective Δ8-THC. Using time-resolved Förster resonance energy transfer (TR-FRET), we developed physiological temperatures. For CB1R, truncated first 90 amino acids its flexible N-terminal domain reduce FRET distance between terbium cryptate (donor) fluorescent (acceptor). full-length CB2R construct was functional without modification due shorter N-terminus. Motulsky-Mahan competition model used analyze endocannabinoids other non-fluorescent ligands. D77 showed nanomolar-range affinity for CB1R (CB1R91-472) (CB2R1-360), displaying competitive with orthosteric exhibited rapid dissociation both CB2R, which were similar fastest dissociating reference compounds. critical accurately determining on- off-rates measured kinetic properties various agonists antagonists temperature sodium ion concentration. k on values molecules varied by three orders magnitude, slowest (HU308) (rimonabant). A strong correlation observed compounds indicating that association rate primarily determines CB1R. Unlike stronger found constant off suggesting dictate overall CB2R. Exploring parameters candidates could help development programs targeting these receptors.

Язык: Английский

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Patent review of cannabinoid receptor type 2 (CB ₂ R) modulators (2016-present)

Expert Opinion on Therapeutic Patents, Год журнала: 2024, Номер 34(8), С. 665 - 700

Опубликована: Июнь 18, 2024

Introduction Cannabinoid receptor type 2 (CB2R), predominantly expressed in immune tissues, is believed to play a crucial role within the body's protective mechanisms. Its modulation holds immense therapeutic promise for addressing wide spectrum of disbiotic conditions, including cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, and autoimmune diseases, as well lung disorders, cancer, pain management.

Язык: Английский

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Photoproximity labeling of endogenous receptors in the live mouse brain in minutes

Nature Chemical Biology, Год журнала: 2024, Номер unknown

Опубликована: Авг. 1, 2024

Язык: Английский

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N-Acyl-N-alkyl/aryl Sulfonamide Chemistry Assisted by Proximity for Modification and Covalent Inhibition of Endogenous Proteins in Living Systems

Accounts of Chemical Research, Год журнала: 2024, Номер unknown

Опубликована: Дек. 11, 2024

ConspectusSelective chemical modification of endogenous proteins in living systems with synthetic small molecular probes is a central challenge biology. Such has variety applications important for biological and pharmaceutical research, including protein visualization, functionalization, proteome-wide profiling enzyme activity, irreversible inhibition activity. Traditional chemistry selective cells largely relies on the high nucleophilicity cysteine residues to ensure target-selectivity site-specificity modification. More recently, lysine residues, which are more abundant surfaces, have attracted attention covalent proteins. However, it been difficult efficiently modify ε-amino groups side-chains, mostly (∼99.9%) protonated thus exhibit low at physiological pH. Our group revealed that

Язык: Английский

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