Development of a Three-Dimensional CysLT1 (LTD4) Antagonist Model with an Incorporated Amino Acid Residue from the Receptor

Zwaagstra, M. E.; Schoenmakers, Saskia H. H. F.; Nederkoorn, Paul H. J.; Gelens, Edith; Timmerman, Henk; Zhang, Ming‐Qiang

doi:10.1021/jm970180w

Cited by 27 publications

(14 citation statements)

References 47 publications

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“…One of the difficulties in the development of a reliable 3D pharmacophoric model for CysLT1 antagonists resides in the flexibility of most antagonists. Furthermore, despite the fact that several antagonists share identical structural elements with the agonists (and a common binding site for agonists and antagonists has been proposed), the existence of structural overlapping between different classes of CysLT receptor antagonists and/or agonists is still debatable [68]. Based on quantitative SAR studies (QSAR), an hypothetical computational model of CysLT1 pocket has been built using almost rigid leukotriene antagonists as template; an arginine residue is incorporated into the preliminary model as an interaction site for the acidic moieties of antagonists [68].…”

Section: Resultsmentioning

confidence: 99%

Forced unbinding of GPR17 ligands from wild type and R255I mutant receptor models through a computational approach

et al. 2010

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BackgroundGPR17 is a hybrid G-protein-coupled receptor (GPCR) activated by two unrelated ligand families, extracellular nucleotides and cysteinyl-leukotrienes (cysteinyl-LTs), and involved in brain damage and repair. Its exploitment as a target for novel neuro-reparative strategies depends on the elucidation of the molecular determinants driving binding of purinergic and leukotrienic ligands. Here, we applied docking and molecular dynamics simulations (MD) to analyse the binding and the forced unbinding of two GPR17 ligands (the endogenous purinergic agonist UDP and the leukotriene receptor antagonist pranlukast from both the wild-type (WT) receptor and a mutant model, where a basic residue hypothesized to be crucial for nucleotide binding had been mutated (R255I) to Ile.ResultsMD suggested that GPR17 nucleotide binding pocket is enclosed between the helical bundle and extracellular loop (EL) 2. The driving interaction involves R255 and the UDP phosphate moiety. To support this hypothesis, steered MD experiments showed that the energy required to unbind UDP is higher for the WT receptor than for R255I. Three potential binding sites for pranlukast where instead found and analysed. In one of its preferential docking conformations, pranlukast tetrazole group is close to R255 and phenyl rings are placed into a subpocket highly conserved among GPCRs. Pulling forces developed to break polar and aromatic interactions of pranlukast were comparable. No differences between the WT receptor and the R255I receptor were found for the unbinding of pranlukast.ConclusionsThese data thus suggest that, in contrast to which has been hypothesized for nucleotides, the lack of the R255 residue doesn't affect the binding of pranlukast a crucial role for R255 in binding of nucleotides to GPR17. Aromatic interactions are instead likely to play a predominant role in the recognition of pranlukast, suggesting that two different binding subsites are present on GPR17.

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Section: Resultsmentioning

confidence: 99%

Forced unbinding of GPR17 ligands from wild type and R255I mutant receptor models through a computational approach

et al. 2010

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“…4) for the leukotriene agonists/antagonists, namely, (1) a lipophilic anchor (side chain), (2) a central flat unit (triene), (3) an ionic pocket (peptide and/or carboxylic acid group), and (4) a hydrophilic site (acidic group). Since this description, other workers have further refined this conceptual model to a three-dimensional one [44,45,46,47]. Interestingly, the three-dimensional models have suggested that all CysLT 1 antagonists may not bind to the same site or in the same manner as the endogenous ligand.…”

Section: Eicosanoid Ligand Modificationsmentioning

confidence: 99%

Structural Manipulation of Eicosanoid Receptors and Cellular Signaling

Brink

2007

The Scientific World JOURNAL

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Eicosanoids are lipid mediators derived from the metabolism of arachidonic acid. These agents are locally released and activate different cell membrane receptors, and the latter are part of the G-protein coupled receptor family. While activation of eicosanoid receptors is associated with a wide variety of actions, there is limited information concerning the structural components of the eicosanoid receptors. To date, our understanding of the eicosanoid ligand-receptor binding interaction has been based on the rhodopsin template model. While receptors in the same family do share a common architecture, there are amino acid residues in the membrane binding pocket that play a key role in ligand recognition as well as the diversity observed in the cellular signaling. In order to understand the eicosanoid receptor binding interaction, attention must be focused on both the nature of the endogenous ligands as well as the template G-protein model that has been proposed. The data derived from chemical alterations in the endogenous ligands, together with the mutagenesis studies involving the structural modifications of the eicosanoid receptors, have suggested a working model of the eicosanoid receptors. However, the data also document various nuances in the receptor structure associated with ligand binding as well as a number of differences that will require further investigation.

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“…Among them, 2‐alkenylquinoline scaffold possess significant bioactivities, as exemplified in Figure . For instances, Montelukast (A 1 , drug for asthma), VUF 5017 (A 2 , CysLT1 antagonist), Chimanine B (A 3 , antileishmanial activity), (A4, FZ‐41) and (A4, KHD161) are utilized in AIDS therapy due to their ability as HIV integrase inhibitors. Additionally, the 2‐styryl quinolines showed anticancer (A 6 &A 7 ) and antifungal (A 8, A 9 ), antiproliferative activity (A 10 ), antifungal (A 5 , A 11 ), antimicrobial l(A 12 ) activities.…”

Section: Introductionmentioning

confidence: 99%

Ru‐Catalyzed Sequential Dehydrogenative Friedlander Reaction/sp³ C–H Activation/Knovenagel Condensation in the Regioselective Synthesis of Chimanine B Analogues

Prameela

Khan

2020

Eur J Org Chem

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Choline chloride (ChCl) based deep eutectic solvent (DES), facilitated the regioselective synthesis of (E)-1-(4-phenyl-2-styrylquinolin-3-yl)ethan-1-one (4), and (E)-3-phenyl-1-(4phenyl-2-((E)-styryl)quinolin-3-yl)prop-2-en-1-ones, (5) from the corresponding 2-amino-5-chloro benzhydrol, (1) in one-pot strategy. The 2-methyl-3-acetylquinoline generated in situ from the 2-amino-5-chloro benzhydrol, (1) and acetyl acetone, (2) via dehydrogenative Friedlander reaction in DES could enable subsequent regio-selective C-2 methyl group sp 3 C-H activation and rapid alkenylation with alcohols, (3) to provide the desired (E)-2-styrylquinolin-3-yl)ethan-1-ones, 4 in short reaction time [a] S.Figure 2. Choline chloride based DESs used in this work.quinolines employing different catalysts like Bronsted acids, [24] transition metals. [25] Friedlander reaction via an oxidative cyclization of 2-aminobenzyl alcohol with either ketones or alcohols were reported by Milstein, [26] Shim, [27] Yus, [28] Verpoort, [29] Kaneda, [30] employing Ru, Ir [31] and Pd [32] catalysis. Ahmed Kamal [33] and co-workers reported 5-nitrofuran-triazole derivatives by multicomponent reactions using CuSO 4 ·5H 2 O/sodium ascorbate/tBuOH/H 2 O. Recently, Xinhua Xu [34] and co-workers reported 3,4-dihydropyrimidin2-(1H)-ones/thiones using an air-stable zirconium(IV)-salophen perfluorooctanesulfonate complex as catalyst. Herein, we reported dehydrogenative cyclization of 2-amino-5-chloro benzhydrol with benzyl alcohol in presence of RuCl 2 (p-Cym) 2 using K 2 CO 3 :Glycol(1:1) and Ch-Cl:Oxalic acid(1:1) DESs. Ru catalyst was employed based on the oxidation studies of both primary and secondary alcohols. [26,27,35] The catalytic pathway of Ru catalysis and its role in the present reaction was evidneced from comparative reaction with and absence of the Ru catalyst, which indicated the necessitiy of RuCl 2 (pCym) 2. In the present study, other catalysts trials were ineffective. Further, optimised mol-% of RuCl 2 (p-Cym) 2 , with 5 mol-% a 60 % yield was observed while 15 mol-% provided 90 % yield (see supporting information). This strategy allowed the primary as well as secondary alcohols oxidization in K 2 CO 3 :Glycerol(1:1) [36] at pH 11 then tuned to acidic pH 1 by addition of Ch-Cl:Oxalic acid(1:1) DES for the in situ generation of quinoline. Likewise, the Ch-Cl:Oxalic acid (1:1) allowed the sp 3 C-H functionalization. Further tuning to the pH 12, with the addition of KOH facilitates the Knovenagel condensation. Results and DiscussionA convenient regioselective one-pot synthesis of Chimanine B analogues, for instances, the (E)-1-(4-phenyl-2-styrylquinolin-3yl)ethan-1-ones (4), and (E)-3-phenyl-1-(4-phenyl-2-((E)-styryl)quinolin-3-yl)prop-2-en-1-ones, (5) are presently reported from the corresponding 2-amino-5-chloro benzhydrol, (1), aromatic alcohols (3) as precursors. Interestingly, the 2-methylquinolone formed in situ in DES underwent regioselective methyl Csp 3 -H activation in one-pot to provide the alkenylated product, 4 in high yields and purity...

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Development of a Three-Dimensional CysLT₁ (LTD₄) Antagonist Model with an Incorporated Amino Acid Residue from the Receptor

Cited by 27 publications

References 47 publications

Forced unbinding of GPR17 ligands from wild type and R255I mutant receptor models through a computational approach

Forced unbinding of GPR17 ligands from wild type and R255I mutant receptor models through a computational approach

Structural Manipulation of Eicosanoid Receptors and Cellular Signaling

Ru‐Catalyzed Sequential Dehydrogenative Friedlander Reaction/sp³ C–H Activation/Knovenagel Condensation in the Regioselective Synthesis of Chimanine B Analogues

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Development of a Three-Dimensional CysLT1 (LTD4) Antagonist Model with an Incorporated Amino Acid Residue from the Receptor

Cited by 27 publications

References 47 publications

Forced unbinding of GPR17 ligands from wild type and R255I mutant receptor models through a computational approach

Forced unbinding of GPR17 ligands from wild type and R255I mutant receptor models through a computational approach

Structural Manipulation of Eicosanoid Receptors and Cellular Signaling

Ru‐Catalyzed Sequential Dehydrogenative Friedlander Reaction/sp3 C–H Activation/Knovenagel Condensation in the Regioselective Synthesis of Chimanine B Analogues

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Development of a Three-Dimensional CysLT₁ (LTD₄) Antagonist Model with an Incorporated Amino Acid Residue from the Receptor

Ru‐Catalyzed Sequential Dehydrogenative Friedlander Reaction/sp³ C–H Activation/Knovenagel Condensation in the Regioselective Synthesis of Chimanine B Analogues