Histamine (re)uptake by astrocytes: an experimental and computational study

Perdan-Pirkmajer, Katja; Mavri, Janez; Kržan, Mojca

doi:10.1007/s00894-009-0624-9

Cited by 19 publications

(21 citation statements)

References 40 publications

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“…The scheme considers five water molecules as a pentamer in the aqueous solution, which conserves the number of hydrogen bonds on both sides of the equation, being in a full analogy with the concept of homodesmotic reactions [ 45 ]. It gives the hydration free energy of –67.5 kcal mol –1 in H 2 O, being in a very close quantitative agreement with the MP2/6–31++G(2d,2p) and Langevin dipole calculated value of –68.6 kcal mol –1 [ 46 ], which lends credence to the computational model applied here.…”

Section: Resultssupporting

confidence: 83%

The Quantum Nature of Drug-Receptor Interactions: Deuteration Changes Binding Affinities for Histamine Receptor Ligands

et al. 2016

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In this article we report a combined experimental and computational study concerning the effects of deuteration on the binding of histamine and two other histaminergic agonists to 3H-tiotidine-labeled histamine H2 receptor in neonatal rat astrocytes. Binding affinities were measured by displacing radiolabeled tiotidine from H2 receptor binding sites present on cultured neonatal rat astrocytes. Quantum-chemical calculations were performed by employing the empirical quantization of nuclear motion within a cluster model of the receptor binding site extracted from the homology model of the entire H2 receptor. Structure of H2 receptor built by homology modelling is attached in the supporting information (S1 Table) Experiments clearly demonstrate that deuteration affects the binding by increasing the affinity for histamine and reducing it for 2-methylhistamine, while basically leaving it unchanged for 4-methylhistamine. Ab initio quantum-chemical calculations on the cluster system extracted from the homology H2 model along with the implicit quantization of the acidic N–H and O–H bonds demonstrate that these changes in the binding can be rationalized by the altered strength of the hydrogen bonding upon deuteration known as the Ubbelohde effect. Our computational analysis also reveals a new mechanism of histamine binding, which underlines an important role of Tyr250 residue. The present work is, to our best knowledge, the first study of nuclear quantum effects on ligand receptor binding. The ligand H/D substitution is relevant for therapy in the context of perdeuterated and thus more stable drugs that are expected to enter therapeutic practice in the near future. Moreover, presented approach may contribute towards understanding receptor activation, while a distant goal remains in silico discrimination between agonists and antagonists based on the receptor structure.

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Section: Resultssupporting

confidence: 83%

The Quantum Nature of Drug-Receptor Interactions: Deuteration Changes Binding Affinities for Histamine Receptor Ligands

et al. 2016

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“…This approach maintains the number of hydrogen bonds on each side of the equation, being fully in line with the model of homodesmotic reactions [48]. For the histamine monocation, it gives the water hydration free energy of -67.5 kcal mol -1 [47], being in a very close quantitative agreement with the MP2/6-31++G(2d,2p) and Langevin dipole calculated value of -68.6 kcal mol -1 [49], thus lending credence to the choice of this computational setup.…”

Section: Resultssupporting

confidence: 74%

Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration

et al. 2020

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We used a combination of density functional theory (DFT) calculations and the implicit quantization of the acidic N–H and O–H bonds to assess the effect of deuteration on the binding of agonists (2-methylhistamine and 4-methylhistamine) and antagonists (cimetidine and famotidine) to the histamine H2 receptor. The results show that deuteration significantly increases the affinity for 4-methylhistamine and reduces it for 2-methylhistamine, while leaving it unchanged for both antagonists, which is found in excellent agreement with experiments. The revealed trends are interpreted in the light of the altered strength of the hydrogen bonding upon deuteration, known as the Ubbelohde effect, which affects ligand interactions with both active sites residues and solvent molecules preceding the binding, thus providing strong evidence for the relevance of hydrogen bonding for this process. In addition, computations further underline an important role of the Tyr250 residue for the binding. The obtained insight is relevant for the therapy in the context of (per)deuterated drugs that are expected to enter therapeutic practice in the near future, while this approach may contribute towards understanding receptor activation and its discrimination between agonists and antagonists.

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“…For such narrowly spaced data, the difficulty lies in the selection of the appropriate computational methodology to (re)produce accurate pK a values, since, for example, brute force calculations employing implicit continuum solvation could yield estimates easily diverging by over 4-5 pK a units. 66 The proper study should involve explicit solvation, to account for the specific solute-solvent interactions, accompanied with the appropriate treatment of electrostatic effects, extensive sampling and thermal averaging. 67−70 These are, however, associated with high computational costs and are beyond the scope of the present manuscript.…”

Section: Resultsmentioning

confidence: 99%

Ring Strain and Other Factors Governing the Basicity of Nitrogen Heterocycles – An Interpretation by Triadic Analysis

Radić¹,

Despotović²,

Vianello³

2012

Croat. Chem. Acta

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Abstract. M06-2X/6-311++G(2df,2pd)//M06-2X/6-31+G(d) computations were employed to investigate the intrinsic gas phase basicity of strained nitrogen heterocycles involving aziridine, azetidine, pyrrolidine and piperidine, together with their N-methyl and N-phenyl derivatives, NR(CH 2 ) n (n = 2-5; R = H, Me and Ph). Basicity constants were compared with the corresponding acyclic counterparts, NR(CH 3 ) 2 (R = H, Me and Ph), and were, based on triadic analysis, resolved into contributions mirroring features of both initial base and the final protonated form as well as their interplay, thus offering quantitative insight into the obtained results. In general, the N-methyl derivatives provided strongest bases investigated here, and, within each group of molecules, the basicity increased on going from three-to six-membered rings, consistent with a decrease in ring strain, with four-membered systems already surpassing or coming close to the basicity of the acyclic gauge molecule. Calculated basicities were found in a very good agreement with available experimental data, except for N-methylazetidine, where a remarkable discrepancy was revealed, suggesting that this system should be experimentally reassessed and its gas-phase basicity parameters revised. Triadic analysis showed different behaviour of individual contributions governing basicities, both among and within distinct families of molecules. It also convincingly demonstrated that, if a proper and a quantitatively accurate interpretation of observed basicity trends is desired, one should not rely only on concepts such as localized reactive hybrid orbitals (RHO) or thus derived nitrogen electron-donating ability (T. Ohwada et al., J. Org. Chem. 69 (2004) 7486), which take into account only properties of the initial base in question, but rather consider protonation reaction in its entirety. (doi: 10.5562/cca2121)

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Histamine (re)uptake by astrocytes: an experimental and computational study

Cited by 19 publications

References 40 publications

The Quantum Nature of Drug-Receptor Interactions: Deuteration Changes Binding Affinities for Histamine Receptor Ligands

The Quantum Nature of Drug-Receptor Interactions: Deuteration Changes Binding Affinities for Histamine Receptor Ligands

Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration

Ring Strain and Other Factors Governing the Basicity of Nitrogen Heterocycles – An Interpretation by Triadic Analysis

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