Molecular Modeling of Histamine Receptors—Recent Advances in Drug Discovery

Mehta, Pakhuri; Filipek, Sławomir

doi:10.3390/molecules26061778

Cited by 18 publications

(13 citation statements)

References 133 publications

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“…In the starting structures of the simulations, histamine formed a salt bridge by its charged amino group with the conserved residue D 3.32 in the orthosteric binding pocket, similarly as postulated in the literature for the entire histamine receptor family [ 78 ]. During the simulations, this interaction performed different dynamics in the H 2 R and H 4 R systems.…”

Section: Resultsmentioning

confidence: 99%

“…In GaMD simulations, a similar preference was observed due to the lower structural flexibility of the H 2 R–mGs and H 4 R–mGsi complexes. In the simulations, a salt bridge between Nα of the endogenous ligand histamine and D 3.32 was present, which is conserved among histamine receptor subtypes [ 60 , 78 ]. Nevertheless, the binding energies of histamine were different in the complexes.…”

Section: Discussionmentioning

confidence: 99%

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Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations

Höring

Conrad

Söldner

et al. 2021

IJMS

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G protein-coupled receptors (GPCRs) are targets of extracellular stimuli and hence occupy a key position in drug discovery. By specific and not yet fully elucidated coupling profiles with α subunits of distinct G protein families, they regulate cellular responses. The histamine H2 and H4 receptors (H2R and H4R) are prominent members of Gs- and Gi-coupled GPCRs. Nevertheless, promiscuous G protein and selective Gi signaling have been reported for the H2R and H4R, respectively, the molecular mechanism of which remained unclear. Using a combination of cellular experimental assays and Gaussian accelerated molecular dynamics (GaMD) simulations, we investigated the coupling profiles of the H2R and H4R to engineered mini-G proteins (mG). We obtained coupling profiles of the mGs, mGsi, or mGsq proteins to the H2R and H4R from the mini-G protein recruitment assays using HEK293T cells. Compared to H2R–mGs expressing cells, histamine responses were weaker (pEC50, Emax) for H2R–mGsi and –mGsq. By contrast, the H4R selectively bound to mGsi. Similarly, in all-atom GaMD simulations, we observed a preferential binding of H2R to mGs and H4R to mGsi revealed by the structural flexibility and free energy landscapes of the complexes. Although the mG α5 helices were consistently located within the HR binding cavity, alternative binding orientations were detected in the complexes. Due to the specific residue interactions, all mG α5 helices of the H2R complexes adopted the Gs-like orientation toward the receptor transmembrane (TM) 6 domain, whereas in H4R complexes, only mGsi was in the Gi-like orientation toward TM2, which was in agreement with Gs- and Gi-coupled GPCRs structures resolved by X-ray/cryo-EM. These cellular and molecular insights support (patho)physiological profiles of the histamine receptors, especially the hitherto little studied H2R function in the brain, as well as of the pharmacological potential of H4R selective drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations

Höring

Conrad

Söldner

et al. 2021

IJMS

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“…Molecular docking refers to the “docking theory” that relies on receptor-ligand interactions to predict the potential binding mode of a compound to a protein [ 16 – 18 ]. Hub genes in the PPI network were selected for molecular docking validation.…”

Section: Methodsmentioning

confidence: 99%

Exploring the Potential Mechanism of Xiaokui Jiedu Decoction for Ulcerative Colitis Based on Network Pharmacology and Molecular Docking

Wang¹,

Liu²,

Sun³

et al. 2021

Journal of Healthcare Engineering

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Introduction. Network pharmacology is in line with the holistic characteristics of TCM and can be used to elucidate the complex network of interactions between disease-specific genes and compounds in TCM herbal medicines. Here, we investigate the pharmacological mechanism of Xiaokui Jiedu decoction (XJD) for the treatment of ulcerative colitis (UC). Methods. The Computational Systems Biology Laboratory Platform (TCMSP) database was searched and screened for the active ingredients of all drugs in XJD. The Uniport database was used to retrieve possible gene targets for the therapeutic effects of XJD. GeneCards, PharmGKB, TTD, and OMIM databases were used to retrieve XJD-related gene targets. A herb-compound-protein network and a protein-protein interaction (PPI) network were constructed, and hub genes were screened for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Finally, molecular docking was performed to validate the interrelationship between disease target proteins and active drug components. Results. A total of 135 XJD potential action targets, 5097 UC-related gene targets, and 103 XJD-UC intersection gene targets were screened. The hub gene targets of XJD that exert therapeutic effects on UC are RB1, MAPK1, TP53, JUN, NR3C1, MAPK3, and ESR1. GO enrichment analysis showed 741 biofunctional enrichments, and KEGG enrichment analysis showed 124 related pathway enrichments. Molecular docking showed that the active components of XJD (β-sitosterol, kaempferol, formononetin, quercetin, and luteolin) showed good binding activities to five of the six hub gene targets. Discussion. The active ingredients of XJD (β-sitosterol, kaempferol, formononetin, quercetin, and luteolin) may regulate the inflammatory and oxidative stress-related pathways of colon cells during the course of UC by binding to the hub gene targets. This may be a potential mechanism of XJD in the treatment of UC.

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“…Histamine is a biologically important amine that exerts its effect through interaction with histamine receptors (H 1 R, H 2 R, H 3 R, and H 4 R) [1][2][3]. Histamine is a mediator of many different physiological processes, such as the contraction of smooth muscle tissues, dilatation of blood vessels, and gastric acid secretion.…”

Section: Introductionmentioning

confidence: 99%

Why Monoamine Oxidase B Preferably Metabolizes N-Methylhistamine over Histamine: Evidence from the Multiscale Simulation of the Rate-Limiting Step

Maršavelski

Mavri

Vianello

et al. 2022

IJMS

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Histamine levels in the human brain are controlled by rather peculiar metabolic pathways. In the first step, histamine is enzymatically methylated at its imidazole Nτ atom, and the produced N-methylhistamine undergoes an oxidative deamination catalyzed by monoamine oxidase B (MAO-B), as is common with other monoaminergic neurotransmitters and neuromodulators of the central nervous system. The fact that histamine requires such a conversion prior to oxidative deamination is intriguing since MAO-B is known to be relatively promiscuous towards monoaminergic substrates; its in-vitro oxidation of N-methylhistamine is about 10 times faster than that for histamine, yet this rather subtle difference appears to be governing the decomposition pathway. This work clarifies the MAO-B selectivity toward histamine and N-methylhistamine by multiscale simulations of the rate-limiting hydride abstraction step for both compounds in the gas phase, in aqueous solution, and in the enzyme, using the established empirical valence bond methodology, assisted by gas-phase density functional theory (DFT) calculations. The computed barriers are in very good agreement with experimental kinetic data, especially for relative trends among systems, thereby reproducing the observed MAO-B selectivity. Simulations clearly demonstrate that solvation effects govern the reactivity, both in aqueous solution as well as in the enzyme although with an opposing effect on the free energy barrier. In the aqueous solution, the transition-state structure involving histamine is better solvated than its methylated analog, leading to a lower barrier for histamine oxidation. In the enzyme, the higher hydrophobicity of N-methylhistamine results in a decreased number of water molecules at the active side, leading to decreased dielectric shielding of the preorganized catalytic electrostatic environment provided by the enzyme. This renders the catalytic environment more efficient for N-methylhistamine, giving rise to a lower barrier relative to histamine. In addition, the transition state involving N-methylhistamine appears to be stabilized by the surrounding nonpolar residues to a larger extent than with unsubstituted histamine, contributing to a lower barrier with the former.

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Molecular Modeling of Histamine Receptors—Recent Advances in Drug Discovery

Cited by 18 publications

References 133 publications

Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations

Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations

Exploring the Potential Mechanism of Xiaokui Jiedu Decoction for Ulcerative Colitis Based on Network Pharmacology and Molecular Docking

Why Monoamine Oxidase B Preferably Metabolizes N-Methylhistamine over Histamine: Evidence from the Multiscale Simulation of the Rate-Limiting Step

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