Molecular modeling and QSAR-based design of histamine receptor ligands

Straßer, Andrea

doi:10.1517/17460440903264972

Cited by 4 publications

(2 citation statements)

References 85 publications

(123 reference statements)

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“…A homology structure of the H 2 receptor was developed earlier [25], which revealed a good agreement with other models reported in the literature [40,41], and was employed here throughout the entire work. The structure of histamine contains an imidazole ring and an aminoethyl side chain, both of which have the ability of accepting a proton, if the medium is acidic enough.…”

Section: Computational Detailssupporting

confidence: 56%

The Effect of Deuteration on the H2 Receptor Histamine Binding Profile: A Computational Insight into Modified Hydrogen Bonding Interactions

2020

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We used a range of computational techniques to reveal an increased histamine affinity for its H2 receptor upon deuteration, which was interpreted through altered hydrogen bonding interactions within the receptor and the aqueous environment preceding the binding. Molecular docking identified the area between third and fifth transmembrane α-helices as the likely binding pocket for several histamine poses, with the most favorable binding energy of −7.4 kcal mol−1 closely matching the experimental value of −5.9 kcal mol−1. The subsequent molecular dynamics simulation and MM-GBSA analysis recognized Asp98 as the most dominant residue, accounting for 40% of the total binding energy, established through a persistent hydrogen bonding with the histamine −NH3+ group, the latter further held in place through the N–H∙∙∙O hydrogen bonding with Tyr250. Unlike earlier literature proposals, the important role of Thr190 is not evident in hydrogen bonds through its −OH group, but rather in the C–H∙∙∙π contacts with the imidazole ring, while its former moiety is constantly engaged in the hydrogen bonding with Asp186. Lastly, quantum-chemical calculations within the receptor cluster model and utilizing the empirical quantization of the ionizable X–H bonds (X = N, O, S), supported the deuteration-induced affinity increase, with the calculated difference in the binding free energy of −0.85 kcal mol−1, being in excellent agreement with an experimental value of −0.75 kcal mol−1, thus confirming the relevance of hydrogen bonding for the H2 receptor activation.

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Section: Computational Detailssupporting

confidence: 56%

The Effect of Deuteration on the H2 Receptor Histamine Binding Profile: A Computational Insight into Modified Hydrogen Bonding Interactions

2020

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“…On the other hand, in silico approaches could assist in the explanation of in vitro tests [35,[40][41][42][43][44][45][46][47]. Very recently, the virtual screening protocol mainly referred in this study [17,19] was retrospectively re-validated [20] using the newest benchmarking dataset provided by Mysinger et al [36].…”

Section: Resultsmentioning

confidence: 99%

Computer-Aided Drug Repurposing: A Cyclooxygenase-2 Inhibitor Celecoxib as a Ligand for Estrogen Receptor Alpha

Istyastono¹,

Riswanto²,

Yuliani³

2015

Indones. J. Chem.

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Molecular Modelling Approaches for the Analysis of Histamine Receptors and Their Interaction with Ligands

Straßer

Wittmann

2017

Handbook of Experimental Pharmacology

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Several experimental techniques to analyse histamine receptors are available, e.g. pharmacological characterisation of known or new compounds by different types of assays or mutagenesis studies. To obtain insights into the histamine receptors on a molecular and structural level, crystal structures have to be determined and molecular modelling studies have to be performed. It is widely accepted to generate homology models of the receptor of interest based on an appropriate crystal structure as a template and to refine the resulting models by molecular dynamic simulations. A lot of modelling techniques, e.g. docking, QSAR or interaction fingerprint methods, are used to predict binding modes of ligands and pharmacological data, e.g. affinity or even efficacy. However, within the last years, molecular dynamic simulations got more and more important: First of all, molecular dynamic simulations are very helpful to refine the binding mode of a ligand to a histamine receptor, obtained by docking studies. Furthermore, with increasing computational performance it got possible to simulate complete binding pathways of ions or ligands from the aqueous extracellular phase into the allosteric or orthosteric binding pocket of histamine receptors.

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Molecular modeling and QSAR-based design of histamine receptor ligands

Cited by 4 publications

References 85 publications

The Effect of Deuteration on the H2 Receptor Histamine Binding Profile: A Computational Insight into Modified Hydrogen Bonding Interactions

The Effect of Deuteration on the H2 Receptor Histamine Binding Profile: A Computational Insight into Modified Hydrogen Bonding Interactions

Computer-Aided Drug Repurposing: A Cyclooxygenase-2 Inhibitor Celecoxib as a Ligand for Estrogen Receptor Alpha

Molecular Modelling Approaches for the Analysis of Histamine Receptors and Their Interaction with Ligands

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