THE ROLE OF ARGININE IN THE BINDING OF LTD4 ANTAGONISTS TO cysLT1 RECEPTORS OF GUINEA PIG LUNG

Zhang, Ming‐Qiang; Zwaagstra, M. E.; Nederkoorn, Paul H. J.; Timmerman, Henk

doi:10.1016/s0960-894x(97)00219-9

Cited by 8 publications

(6 citation statements)

References 23 publications

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“…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. This had been suggested in a previously published report using guinea pig lung preparations [48]. In this latter study, the authors showed that the potency of ICI198615 decreased markedly in displacing bound [ 3 H]-LTD 4 following blockade of the arginine residues, whereas LTD 4 was unaffected.…”

Section: Eicosanoid Ligand Modificationssupporting

confidence: 63%

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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Section: Eicosanoid Ligand Modificationssupporting

confidence: 63%

Structural Manipulation of Eicosanoid Receptors and Cellular Signaling

Brink

2007

The Scientific World JOURNAL

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“…Preliminary experiments with an arginine-masking agent (phenylglyoxal) demonstrated that the potency of tested antagonists ICI 198,615 and 7 in displacing bound [ 3 H]-LTD 4 decreased over 5 log units after the blockade of arginine residues. 55 Since the affinity of LTD 4 itself was little affected, arginine residues were suggested to be important for the binding of antagonists but not for LTD 4 . More experiments are necessary to establish the role of an arginine in interaction with CysLT 1 antagonists.…”

Section: Discussionmentioning

confidence: 99%

“…The selection of an arginine residue as a basic interaction site for the acidic residues of the ligands, in the CysLT 1 antagonist model was guided by literature reports on the importance of this residue in several G-protein-coupled receptors in binding to their ligands, the complementarity of the electrostatic potentials of the antagonist conformations and arginine, and the potential formation of multiple hydrogen bonds. Preliminary experiments with an arginine-masking agent (phenylglyoxal) demonstrated that the potency of tested antagonists ICI 198,615 and 7 in displacing bound [ 3 H]LTD 4 decreased over 5 log units after the blockade of arginine residues . Since the affinity of LTD 4 itself was little affected, arginine residues were suggested to be important for the binding of antagonists but not for LTD 4 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1998

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This paper describes the molecular modeling of leukotriene CysLT1 (or LTD4) receptor antagonists. Several different structural classes of CysLT1 antagonists were superimposed onto the new and highly rigid CysLT1 antagonist 8-carboxy-3'-[2-(2-quinolinyl)ethenyl]flavone (1, VUF 5017) to generate a common pharmacophoric arrangement. On the basis of known structure-activity relationships of CysLT1 antagonists, the quinoline nitrogen (or a bioisosteric equivalent thereof) and an acidic function were taken as the matching points. In order to optimize the fitting of acidic moieties of all antagonists, an arginine residue from the receptor was proposed as the interaction site for the acidic moieties. Incorporation of this amino acid residue into the model revealed additional interactions between the guanidine group and the nitrogen atoms of quinoline-containing CysLT1 antagonists. In some cases, the arginine may even interact with pi-clouds of phenyl residues of CysLT1 antagonists. The alignment of Montelukast (MK-476) suggests the presence of an additional pocket in the binding site for CysLT1 antagonists. The derived model should be useful for a better understanding of the molecular recognition of the leukotriene CysLT1 receptor.

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“…The main difficulty in the development of reliable alignments is not only the flexibility of most antagonists 16 but also the ambiguity of the receptor-ligand interactions. 10,12 Therefore, despite the consequent limitations, we preferred to obtain models based on series of congeners which may act in a similar preferential fashion, rather than considering structurally diverse antagonists. Some compounds having the template quinolinyl-(bridged)aryl structure are known to tightly bind the pLT receptors, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…The number and subtypes of pLT receptors in the airways are still a matter of debate with evidence on structurally different receptors in human and guinea pig airways. − Indeed, there is hardly any direct evidence that the leukotriene D 4 (LTD 4 ) receptor−antagonist interaction is unique or that all of the known LTD 4 receptor−antagonist compounds act in a similar preferential fashion. , Despite being structurally diverse, most of the known ligands show some common features, i.e. a common overall shape, which may match the leukotriene structure, based on an acidic function connected to a sequence of ring templates.…”

Section: Introductionmentioning

confidence: 99%

Derivation of Pharmacophore and CoMFA Models for Leukotriene D₄ Receptor Antagonists of the Quinolinyl(bridged)aryl Series

Palomer¹,

Pascual²,

Cabré³

et al. 2000

J. Med. Chem.

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The present work focuses on the study of the three-dimensional (3D) structural requirements for the leukotriene D(4) (LTD(4)) antagonistic activity of compounds having the basic quinolinyl(bridged)aryl framework. An approach combining pharmacophore mapping, molecule alignment, and CoMFA models was used to derive a hypothesis for a series of LTD(4) antagonists having the basic diaryl-bridged framework. In this compound series, the produced pharmacophore hypotheses have shown to yield molecule alignments suitable to derive valuable CoMFA models. Model selection focused on (1) obtention of coherent modeling results, (2) consistency with the available SAR data, and (3) ability to predict the activity of an independent set of congeneric molecules. This approach resulted in a combined pharmacophore and CoMFA model that can generally represent the antagonistic activity within a log unit of the measured value for compounds of the series. The resulting pharmacophore (model C) consists of an acidic or negative ionizable function (AC), a hydrogen-bond acceptor (HBA), and three hydrophobic regions (HY) and produces chemically meaningful alignments with the most active compounds of the series mapping the pharmacophore in a extended energetically favorable conformation.

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THE ROLE OF ARGININE IN THE BINDING OF LTD4 ANTAGONISTS TO cysLT1 RECEPTORS OF GUINEA PIG LUNG

Cited by 8 publications

References 23 publications

Structural Manipulation of Eicosanoid Receptors and Cellular Signaling

Structural Manipulation of Eicosanoid Receptors and Cellular Signaling

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

Derivation of Pharmacophore and CoMFA Models for Leukotriene D₄ Receptor Antagonists of the Quinolinyl(bridged)aryl Series

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THE ROLE OF ARGININE IN THE BINDING OF LTD4 ANTAGONISTS TO cysLT1 RECEPTORS OF GUINEA PIG LUNG

Cited by 8 publications

References 23 publications

Structural Manipulation of Eicosanoid Receptors and Cellular Signaling

Structural Manipulation of Eicosanoid Receptors and Cellular Signaling

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

Derivation of Pharmacophore and CoMFA Models for Leukotriene D4 Receptor Antagonists of the Quinolinyl(bridged)aryl Series

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

Derivation of Pharmacophore and CoMFA Models for Leukotriene D₄ Receptor Antagonists of the Quinolinyl(bridged)aryl Series