Delineation of Receptor‐Ligand Interactions at the Human Histamine H<sub>1</sub> Receptor by a Combined Approach of Site‐Directed Mutagenesis and Computational Techniques – or – How to Bind the H<sub>1</sub> Receptor

Jongejan, Aldo; Leurs, Rob

doi:10.1002/ardp.200400998

Cited by 30 publications

(29 citation statements)

References 64 publications

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“…The alignment was performed with SYBYL7.0 using the MultiFit tool. Since the binding mode of histamine 1 is different from the binding mode of the histamine partial structure in dimeric histaprodifen, histamine was docked manually in its bioactive conformation as described [10] to the H 1 Rs. The histamine derivatives 2R and 2S were aligned to histamine.…”

Section: Receptor Models and Ligand Alignmentmentioning

confidence: 99%

3D‐QSAR CoMFA Study to Predict Orientation of Suprahistaprodifens and Phenoprodifens in the Binding‐Pocket of Four Histamine H₁‐Receptor Species

Straßer

Wittmann

2010

Molecular Informatics

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Several phenylhistamines and histaprodifens were identified to act as (partial) agonists at the histamine H1 -receptor (H1 R). The large diversity of these compounds led to pKi values in a range between 4.5-7.5 at human, rat, bovine and guinea-pig histamine H1 R. Hybrid molecules, consisting of two different H1 R-agonist partial structures, like suprahistaprodifens or phenoprodifens for example, or compounds with a dimeric histamine moiety are able to bind in two different orientations into the binding-pocket of the H1 R. In order to predict the percentage of ligand bound in orientation 1 or in orientation 2, 3D-QSAR studies at four H1 R species were performed. The training set contains ligands which can only bind in one orientation and the test set all ligands with two possible orientations. In general, the predicted pKi values of the test compounds were in good correlation to the experimental ones. Additionally, the predicted pKi values for all ligands with two possible orientations were used to calculate the percentage of the hybrid ligands bound in orientation 1 and 2. Our models suggest that the preferred orientation of these hybrid molecules is dependent on ligand and H1 R species.

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Section: Receptor Models and Ligand Alignmentmentioning

confidence: 99%

3D‐QSAR CoMFA Study to Predict Orientation of Suprahistaprodifens and Phenoprodifens in the Binding‐Pocket of Four Histamine H₁‐Receptor Species

Straßer

Wittmann

2010

Molecular Informatics

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“…In living organisms, the copper (II) ion complexes have a direct effect on the interaction of metal with proteins [6][7][8][9][10][11][12]. Therefore, the geometry structure of the Cu(II) ion and its surrounding represent a model which have an effect on the metal-enzyme interactions [2,13].…”

Section: Introductionmentioning

confidence: 99%

“…The crystal compound has N(8)-Cu-N(1) 92.57° and Cl(1)-Cu-Cl(2) 88.81°. So, the Cu(II) ion bridges with N and Cl atoms in the axial conformation (N-Cu-N and Cl-C-Cl angles near 90º ) (Table 2a, entries [10][11][12][13][14][15][16][17][18][19][20][21][22][23].…”

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confidence: 99%

Molecular and Semi-Empirical Mechanic Studies of Copper-Histamine Chloride Complex

Mahboub

Louhibi

2016

ILCPA

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Abstract. In the present work, we describe and characterized the molecular structure and molecular orbital of Cu(His)Cl 2 by two methods: molecular mechanic and semi-empirical PM3 simulations. First, we determine the geometry structural properties of the Cu(Hist)Cl 2 complex by molecular mechanic method. Then we compare the calculations method with the experimental data of Cu(His)Cl 2 crystal complex. We find that the optimized parameters obtained by MM method are in good agreement with those observed experimentally. After, we evaluate the quantum chemical parameters using PM3 simulations and we discuss the chemical reactivity of Cu(II) ion and the stability of Cu(His)Cl 2 molecule. We obtain a large gap with PM3 method. We evaluate the electrophilicity index of the complex. We also calculate the deformation energy. We deduce from quantum calculations that Cu(Hist)Cl 2 molecule has high chemical reactivity and is more stable. Finally, we calculate the relative and average errors to estimate the quality of each method. We show that average errors vary as follow: for bonds are 7.833 and 2.692 %, and for angles are 7.755 and 5.309 % using MM+ and PM3 respectively. We conclude that both molecular mechanic and semi-empirical calculations agree very well with the experimental data.

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“…The aim of this study was to analyze the binding process of dimeric histaprodifen, one of the largest H 1 -receptor ligands known, to guinea-pig (gp) H 1 R. Site directed mutagenesis studies revealed that the exchange of asparagine to serine at position 2.61 is responsible for the species differences in pharmacology of dimeric histaprodifen between hH 1 R and gpH 1 R [33]. Within further mutagenesis studies, the influence of other amino acids onto pharmacology of dimeric histaprodifen at hH 1 R was analyzed [34,35]. These studies revealed an essential influence of Asp 3.32 and Phe 6.52 onto binding of dimeric histaprodifen to hH 1 R [34,35].…”

Section: Introductionmentioning

confidence: 99%

In silico analysis of the histaprodifen induced activation pathway of the guinea-pig histamine H1-receptor

Straßer

Wittmann

2010

J Comput Aided Mol Des

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The binding of (partial) agonists in the binding pocket of biogenic amine receptors induces a conformational change from the inactive to the active state of the receptors. There is only little knowledge about the binding pathways of ligands into binding pocket on molecular level. So far, it was not possible with molecular dynamic simulations to observe the ligand binding and receptor activation. Furthermore, there is nearly nothing known, in which state of ligand binding, the receptor gets activated. The aim of this study was to get more detailed insight into the process of ligand binding and receptor activation. With the recently developed LigPath algorithm, we scanned the potential energy surface of the binding process of dimeric histaprodifen, a partial agonist at the histamine H(1)-receptor, into the guinea pig histamine H(1)-receptor, taking also into account the receptor activation. The calculations exhibited large conformational changes of Trp(6.48) and Phe(6.55) during ligand binding and receptor activation. Additionally, conformational changes were also observed for Phe(6.52), Tyr(6.51) and Phe(6.44). Conformational changes of Trp(6.48) and Phe(6.52) are discussed in literature as rotamer toggle switch in context with receptor activation. Additionally, the calculations indicate that the binding of dimeric histaprodifen, accompanied by receptor activation is energetically preferred. In general, this study gives new, theoretical insights onto ligand binding and receptor activation on molecular level.

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Delineation of Receptor‐Ligand Interactions at the Human Histamine H₁ Receptor by a Combined Approach of Site‐Directed Mutagenesis and Computational Techniques – or – How to Bind the H₁ Receptor

Cited by 30 publications

References 64 publications

3D‐QSAR CoMFA Study to Predict Orientation of Suprahistaprodifens and Phenoprodifens in the Binding‐Pocket of Four Histamine H₁‐Receptor Species

3D‐QSAR CoMFA Study to Predict Orientation of Suprahistaprodifens and Phenoprodifens in the Binding‐Pocket of Four Histamine H₁‐Receptor Species

Molecular and Semi-Empirical Mechanic Studies of Copper-Histamine Chloride Complex

In silico analysis of the histaprodifen induced activation pathway of the guinea-pig histamine H1-receptor

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Delineation of Receptor‐Ligand Interactions at the Human Histamine H1 Receptor by a Combined Approach of Site‐Directed Mutagenesis and Computational Techniques – or – How to Bind the H1 Receptor

Cited by 30 publications

References 64 publications

3D‐QSAR CoMFA Study to Predict Orientation of Suprahistaprodifens and Phenoprodifens in the Binding‐Pocket of Four Histamine H1‐Receptor Species

3D‐QSAR CoMFA Study to Predict Orientation of Suprahistaprodifens and Phenoprodifens in the Binding‐Pocket of Four Histamine H1‐Receptor Species

Molecular and Semi-Empirical Mechanic Studies of Copper-Histamine Chloride Complex

In silico analysis of the histaprodifen induced activation pathway of the guinea-pig histamine H1-receptor

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Delineation of Receptor‐Ligand Interactions at the Human Histamine H₁ Receptor by a Combined Approach of Site‐Directed Mutagenesis and Computational Techniques – or – How to Bind the H₁ Receptor

3D‐QSAR CoMFA Study to Predict Orientation of Suprahistaprodifens and Phenoprodifens in the Binding‐Pocket of Four Histamine H₁‐Receptor Species

3D‐QSAR CoMFA Study to Predict Orientation of Suprahistaprodifens and Phenoprodifens in the Binding‐Pocket of Four Histamine H₁‐Receptor Species