Recent progress in the use of diaziridine-based sweetener derivatives to elucidate the chemoreception mechanism of the sweet taste receptor

Hashimoto, Makoto; Nakagita, Tomoya; Misaka, Takumi

doi:10.1039/d1ra04831g

Cited by 7 publications

(10 citation statements)

References 89 publications

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“…The replacement of −NH 3 + by CH 2 −NH 3 + ( 7) is also carried out as another approach to extend the reach of the carbomethoxy arm, preserving the key hydrogen bonds involving Asp278, Ser303, and Asp307. The incorporation of a methyl group to the βcarbon is also considered in order to promote hydrophobic interactions toward nearby residues (8). The last structural modification concerns the elongation of the ligand backbone by a methylene group (−CH 2 −) between the carbonyl and the α-carbon (9).…”

Section: Resultsmentioning

confidence: 99%

“…The last structural modification concerns the elongation of the ligand backbone by a methylene group (−CH 2 −) between the carbonyl and the α-carbon ( 9 ). Given that aspartame derivatives with substituents in the phenyl moiety exhibit small sweet potency compared to the parent compound, such a type of modifications is not considered. ,, A schematic representation of 1 derivatives is presented in Figure ; the corresponding RMSD and MD- igm results are shown in Figure . The atomic decomposition scheme of the derivatives is presented in Figure S1.…”

Section: Resultsmentioning

confidence: 99%

“…The steady increase in daily sugar consumption over recent decades has contributed to the obesity crisis and the early onset of type 2 diabetes and other chronic diseases. − This situation has prompted the development of noncaloric sweeteners like the amino-acid-based sweetener aspartame (Figure a), a methyl ester of a dipeptide composed of aspartic acid and phenylalanine, which is extensively used in reduced calorie food and beverage products aimed for diabetes patients, or more generally for weight loss. , In the field of biochemistry, the discovery of aspartame has stimulated 3D structure–activity relationship research for a better understanding of the origin of the sweet taste sensation. − …”

Section: Introductionmentioning

confidence: 99%

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Revisiting the Sweet Taste Receptor T1R2-T1R3 through Molecular Dynamics Simulations Coupled with a Noncovalent Interactions Analysis

et al. 2023

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It is nowadays widely accepted that sweet taste perception is elicited by the activation of the heterodimeric complex T1R2-T1R3, customarily known as sweet taste receptor (STR). However, the interplay between STR and sweeteners has not yet been fully clarified. Here through a methodology coupling molecular dynamics and the independent gradient model (igm) approach we determine the main interacting signatures of the closed (active) conformation of the T1R2 Venus flytrap domain (VFD) toward aspartame. The igm methodology provides a rapid and reliable quantification of noncovalent interactions through a score (Δg inter) based on the attenuation of the electronic density gradient when two molecular fragments approach each other. Herein, this approach is coupled to a 100 ns molecular dynamics simulation (MD-igm) to explore the ligand–cavity contacts on a per-residue basis as well as a series of key inter-residue interactions that stabilize the closed form of VFD. We also apply an atomic decomposition scheme of noncovalent interactions to quantify the contribution of the ligand segments to the noncovalent interplay. Finally, a series of structural modification on aspartame are conducted in order to obtain guidelines for the rational design of novel sweeteners. Given that innovative methodologies to reliably quantify the extent of ligand–protein coupling are strongly demanded, this approach combining a noncovalent analysis and MD simulations represents a valuable contribution, that can be easily applied to other relevant biomolecular systems.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Revisiting the Sweet Taste Receptor T1R2-T1R3 through Molecular Dynamics Simulations Coupled with a Noncovalent Interactions Analysis

et al. 2023

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“…Some of them exhibit a bioactive property, being investigated in medicinal chemistry . Moreover, not only are diazirines the prime precursors for generating transient carbene species via the cleavage of C–N bonds, which have been widely utilized in synthetic chemistry but also they have applications in photoaffinity labeling …”

Section: Introductionmentioning

confidence: 99%

“…8 Moreover, not only are diazirines the prime precursors for generating transient carbene species via the cleavage of C−N bonds, which have been widely utilized in synthetic chemistry but also they have applications in photoaffinity labeling. 9 The heavier analogues silacyclopropanes, 10 silacyclopropenes, 11 phosphiranes, 12 phosphirenes, 12b,13 thiiranes, 14 and thiirenes 15 have also been enthusiastically studied, and their Published: June 8, 2023 utilities have been underpinned by a number of applications. For instance, metal-catalyzed silylene transfer from silacyclopropanes to alkenes allows access to novel silacycles.…”

Section: Introductionmentioning

confidence: 99%

Three-Membered Aluminacycles

Yan

Kinjo

2023

J. Am. Chem. Soc.

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Three-membered-ring scaffolds of carbocycles, namely, cyclopropanes and cyclopropenes, are ubiquitous in natural products and pharmaceutical molecules. These molecules exhibit a peculiar reactivity, and their applications as synthetic intermediates and versatile building blocks in organic synthesis have been extensively studied over the past century. The incorporation of heteroatoms into three-membered cyclic structures has attracted significant attention, reflecting fundamental differences in their electronic/geometric structures and reactivities compared to their carbon congeners and their associated potential for exploitation in applications. Recently, the chemistry of low-valent aluminum species, alumylenes, dialumenes, and aluminyl anions, has dramatically developed, which has allowed access to hitherto unprecedented aluminacycles. This Perspective focuses upon advances in the chemistry of three-membered aluminacycles, including their synthetic protocols, spectroscopic and structural properties, and reactivity toward various substrates and small molecules.

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Identification of potential targets against SARS‐CoV‐2 of antiviral drugs based on photoaffinity probes

Wang

Pan

et al. 2023

Drug Development Research

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Facing the sudden outbreak of coronavirus disease 2019 (COVID‐19), it is extremely urgent to develop effective antiviral drugs against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Drug repurposing is a promising strategy for the treatment of COVID‐19. To identify the precise target protein of marketed medicines, we initiate a chemical biological program to identify precise target of potential antivirus drugs. In this study, two types of recombinant human coronavirus SARS‐CoV‐2 RdRp protein capturing probes with various photoaffinity labeling units were designed and synthesized based on the structure of FDA‐approved drugs stavudine, remdesivir, acyclovir, and aladenosine. Fortunately, it was found that one novel photoaffinity probe, RD‐1, could diaplayed good affinity with SARS‐CoV‐2 RdRp around the residue ARG_553. In addition, RD‐1 probe also exhibited potent inhibitory activity against 3CLpro protease. Taken together, our findings will elucidate the structural basis for the efficacy of marketed drugs, and explore a rapid and efficient strategy of drug repurposing based on the identification of new targets. Moreover, these results could also provide a scientific basis for the clinical application of marketed drugs.

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Recent progress in the use of diaziridine-based sweetener derivatives to elucidate the chemoreception mechanism of the sweet taste receptor

Abstract: The review summarized recent progress for the elucidation of the chemoreception mechanism of sweet taste receptor–sweetener interactions with photoaffinity labeling.

Cited by 7 publications

References 89 publications

Revisiting the Sweet Taste Receptor T1R2-T1R3 through Molecular Dynamics Simulations Coupled with a Noncovalent Interactions Analysis

Revisiting the Sweet Taste Receptor T1R2-T1R3 through Molecular Dynamics Simulations Coupled with a Noncovalent Interactions Analysis

Three-Membered Aluminacycles

Identification of potential targets against SARS‐CoV‐2 of antiviral drugs based on photoaffinity probes

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