Direct evidence of edge-to-face CH/π interaction for PAR-1 thrombin receptor activation

Asai, Daisuke; Inoue, N.; Sugiyama, Makiko; Fujita, Teizo; Matsuyama, Yutaka; Liu, Xiaohui; Matsushima, Ayami; Nose, Takeru; Costa, Tommaso; Shimohigashi, Yasuyuki

doi:10.1016/j.bmc.2021.116498

Cited by 4 publications

(5 citation statements)

References 29 publications

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“…As shown in Figure A (inset Table), the introduction of a 5O W at position 2 slightly destabilized the fold of hairpin 1b . In contrast, the introduction of a small but highly electronegative fluorine of 5F W at position 17 created an unexpectedly larger destabilization in 1c . This effect was attributed to \electronic repulsion, as the fluorine substituent was in close proximity to the cross-strand pyrrole nitrogen of W2 (see increased internal entropy in Table S3, Supporting Information).…”

Section: Results and Discussionmentioning

confidence: 99%

“…In contrast, the introduction of a small but highly electronegative fluorine of 5F W at position 17 created an unexpectedly larger destabilization in 1c. 62 This effect was attributed to \electronic repulsion, as the fluorine substituent was in close proximity to the cross-strand pyrrole nitrogen of W2 (see increased internal entropy in Table S3, Supporting Information). Then we combined these two modifications to increase the noncovalent π interactions between the 5O W/ 5F W pairs.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Tunable CH/π Interactions within a Tryptophan Zipper Motif to Stabilize the Fold of Long β-Hairpin Peptides

Richaud,

Mandal,

Das

et al. 2023

ACS Chem. Biol.

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The tryptophan zipper (Trpzip) is an iconic folding motif of β-hairpin peptides capitalizing on two pairs of cross-strand tryptophans, each stabilized by an aromatic–aromatic stacking in an edge-to-face (EtF) geometry. Yet, the origins and the contribution of this EtF packing to the unique Trpzip stability remain poorly understood. To address this question of structure–stability relationship, a library of Trpzip hairpins was developed by incorporating readily accessible nonproteinogenic tryptophans of varying electron densities. We found that each EtF geometry was, in fact, stabilized by an intricate combination of XH/π interactions. By tuning the π-electron density of Trp face rings, CH/π interactions are strengthened to gain additional stability. On the contrary, our DFT calculations support the notion that Trp edge modulations are challenging due to their simultaneous paradoxical engagement as H-bond donors in CH/π and acceptors in NH/π interactions.

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Section: Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Tunable CH/π Interactions within a Tryptophan Zipper Motif to Stabilize the Fold of Long β-Hairpin Peptides

Richaud,

Mandal,

Das

et al. 2023

ACS Chem. Biol.

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“…We speculate that the weaker edge–to–face interaction obtained in the simulation than that in the crystal structures resulted from the solvent environment. However, the edge–to–face interaction plays an important role in ligand binding with proteins. − Furthermore, the dimethyl phenyl and ethyl amide groups have been applied to increase the selectivity between BRD4-BD1 and BRD4-BD2. − Thus, this edge–to–face interaction warrants further investigation in future studies.…”

Section: Resultsmentioning

confidence: 99%

Selectivity Mechanism of Pyrrolopyridone Analogues Targeting Bromodomain 2 of Bromodomain-Containing Protein 4 from Molecular Dynamics Simulations

Shi,

Zheng,

Zhou

et al. 2023

ACS Omega

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Bromodomain and extra-terminal domain (BET) proteins play an important role in epigenetic regulation and are linked to several diseases; therefore, they are interesting targets. BET has two bromodomains: bromodomain 1 (BD1) and BD2. Selective targeting of BD1 or BD2 may produce different activities and greater effects than pan-BD inhibitors. However, the selective mechanism of the specific core must be studied at the atomic level. This study determined the effectiveness of pyrrolopyridone analogues to selectively inhibit BD2 using a pan-BD inhibitor (ABBV-075) and a selective-BD2 inhibitor (ABBV-744). Molecular dynamics simulations and calculations of binding free energies were used to systematically study the selectivity of BD2 inhibition by the pyrrolopyridone analogues. Overall, the pyrrolopyridone analogue inhibitors targeting BD2 interacted mainly with the following amino acid pairs between bromodomain-containing protein 4 (BRD4)-BD1 and BRD4-BD2 complexes: I146/V439, N140/N433, D144/H437, P82/P375, V87/V380, D88/D381, and Y139/Y432. The pyrrolopyridone analogues targeting BRD4-BD2 were divided into five regions based on selectivity mechanism. These results suggest that the R3 and R5 regions of pyrrolopyridone analogues can be modified to improve the selectivity between BRD4-BD1 and BRD4-BD2. The selectivity of BD2 inhibition by pyrrolopyridone analogues can be used to design novel BD2 inhibitors based on a pyrrolopyridone core.

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“…The peptide ligand which has a hydrogen atom at the para ─ position of the benzene ring in the side chain of phenylalanine did not activate the receptor. 8 This result means that the hydrogen atom at the para ─ position is not required for receptor activation. On the other hand, a hydrogen atom at either the ortho ─ or meta ─ positions is essential for thrombin receptor activation.…”

Section: ． Special Activity Enhancement Due To Fluorine In Peptide Li...mentioning

confidence: 98%

Novel Estrogen Receptor Inhibitory Mechanism for Halogen-containing Endocrine-disrupting Chemicals Discovered by Computer Simulation

Matsushima

2023

J. Synth. Org. Chem. Jpn.

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Bisphenol A (BPA) is a component used in the manufacture of polycarbonate plastics and epoxy resins around the world; however, it is also well─ known as one of the most notorious endocrine─ disrupting chemicals. To avoid using BPA as an ingredient, various BPA derivatives and related compounds have been synthesized and the use of these for making polymers has grown signi cantly; however, the safety of these BPA derivatives, also known as next─ generation bisphenols, has not been fully evaluated. We hypothesized that the bisphenol moiety is a privileged structure for binding to nuclear receptors. Here, we summarize the binding ability of next─ generation bisphenols to estrogen receptors and show that halogen─ containing bisphenols act as coactivator binding inhibitors for estrogen receptor β.

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Direct evidence of edge-to-face CH/π interaction for PAR-1 thrombin receptor activation

Cited by 4 publications

References 29 publications

Tunable CH/π Interactions within a Tryptophan Zipper Motif to Stabilize the Fold of Long β-Hairpin Peptides

Tunable CH/π Interactions within a Tryptophan Zipper Motif to Stabilize the Fold of Long β-Hairpin Peptides

Selectivity Mechanism of Pyrrolopyridone Analogues Targeting Bromodomain 2 of Bromodomain-Containing Protein 4 from Molecular Dynamics Simulations

Novel Estrogen Receptor Inhibitory Mechanism for Halogen-containing Endocrine-disrupting Chemicals Discovered by Computer Simulation

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