Efforts to Understand the Molecular Basis of Hypertension Through Drug:Membrane Interactions

Mavromoustakos, Thomas; Zoumpoulakis, Panagiotis; Kyrikou, Ioanna; Ζώγα, Αναστασία; Siapi, Eleni; Zervou, Maria; Daliani, I.; Dimitriou, D.; Pitsas, A.; Kamoutsis, C.; Laggner, Peter

doi:10.2174/1568026043451339

Cited by 22 publications

(24 citation statements)

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“…Furthermore, losartan decreased the mobility of the lipid molecules, particularly the mobility of the alkyl chains, and increased the order of the bilayer. The information derived from the presented study is in agreement with the combined results obtained with DSC, Raman, 13 C-MAS, 31 P CP/MAS NMR, and EPR, all concluding that losartan anchors in the realm of the headgroup region (34,35).…”

Section: Discussionsupporting

confidence: 88%

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Development of a CP 31P NMR Broadline Simulation Methodology for Studying the Interactions of Antihypertensive AT1 Antagonist Losartan with Phospholipid Bilayers

Fotakis

Christodouleas

Chatzigeorgiou

et al. 2009

Biophysical Journal

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A cross-polarization (CP) (31)P NMR broadline simulation methodology was developed for studying the effects of drugs in phospholipids bilayers. Based on seven-parameter fittings, this methodology provided information concerning the conformational changes and dynamics effects of losartan in the polar region of the dipalmitoylphosphatidylcholine bilayers. The test molecule for this study was losartan, an antihypertensive drug known to exert its effect on AT(1) transmembrane receptors. The results were complemented and compared with those of differential scanning calorimetry, solid-state (13)C NMR spectroscopy, Raman spectroscopy, and electron spin resonance. More specifically, these physical chemical methodologies indicated that the amphipathic losartan molecule interacts with the hydrophilic-head zone of the lipid bilayers. The CP (31)P NMR broadline simulations showed that the lipid molecules in the bilayers containing losartan displayed greater collective tilt compared to the tilt displayed by the load-free bilayers, indicating improved packing. The Raman results displayed a decrease in the trans/gauche ratio and increased intermolecular interactions of the acyl chains in the liquid crystalline phase. Additional evidence, suggesting that losartan possibly anchors in the realm of the headgroup, was derived from upfield shift of the average chemical shift sigma(iso) of the (31)P signal in the presence of losartan and from shift of the observed peak at 715 cm(-1) attributed to C-N stretching in the Raman spectra.

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Section: Discussionsupporting

confidence: 88%

“…The application of the CP 31 P NMR broadline simulations suggested that losartan was localized in the zone of the hydrophilic headgroup (34,35). Furthermore, losartan decreased the mobility of the lipid molecules, particularly the mobility of the alkyl chains, and increased the order of the bilayer.…”

Section: Discussionmentioning

confidence: 99%

Development of a CP 31P NMR Broadline Simulation Methodology for Studying the Interactions of Antihypertensive AT1 Antagonist Losartan with Phospholipid Bilayers

Fotakis

Christodouleas

Chatzigeorgiou

et al. 2009

Biophysical Journal

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“…Furthermore, since MD analysis has been performed for both CB1 and CB2 receptors, results can be useful for synthetic chemists to produce more selective CB compounds. The localization of AMG3 at the binding sites of the CB1 and CB2 receptors are in the core region of TM3-TM7 in accordance with reported biophysical crystallographic and modelling studies [102][103][104][105][106][107][108][109][110][111][112][113][114][115] (Fig. 3).…”

Section: Strategy Applied For a System-iisupporting

confidence: 89%

Strategies in the Rational Drug Design

Mavromoustakos

Durdağı²,

Koukoulitsa³

et al. 2011

CMC

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Rational design is applied in the discovery of novel lead drugs. Its rapid development is mainly attributed to the tremendous advancements in the computer science, statistics, molecular biology, biophysics, biochemistry, medicinal chemistry, pharmacokinetics and pharmacodynamics experienced in the last few decades. The promising feature that characterizes the application of rational drug design is that it uses for developing potential leads in drug discovery all known theoretical and experimental knowledge of the system under study. The utilization of the knowledge of the molecular basis of the system ultimately aims to reduce human power cost, time saving and laboratory expenses in the drug discovery. In this review paper various strategies applied for systems which include: (i) absence of knowledge of the receptor active site; (ii) the knowledge of a homology model of a receptor, (iii) the knowledge of the experimentally determined (i.e. X-ray crystallography, NMR spectroscopy) coordinates of the active site of the protein in absence and (iv) the presence of the ligand will be analyzed.

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“…Such pathway has been proposed for a number of ligands (Fig. 5B) like the endogenous CB 1 cannabinoid receptor agonist anandamide, the synthetic ␤ 2 -adrenergic receptor agonist salmeterol, the AT 1 -type angiotensin II receptor antagonist losartan and the D 2 -dopamine receptor antagonist spiperone (Anderson, 1993;Anderson et al, 1994;Theodoropoulou and Marsh, 1999;Zoumpoulakis et al, 2003;Mavromoustakos et al, 2004;Makriyannis et al, 2005;Tian et al, 2005;Packeu et al, 2008). Anadamantine (Fig.…”

Section: Lateral Translocation Between the Receptor's Transmembrane ␣mentioning

confidence: 99%

Ligands, their receptors and … plasma membranes

Vauquelin

Packeu

2009

Molecular and Cellular Endocrinology

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Efforts to Understand the Molecular Basis of Hypertension Through Drug:Membrane Interactions

Cited by 22 publications

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Development of a CP 31P NMR Broadline Simulation Methodology for Studying the Interactions of Antihypertensive AT1 Antagonist Losartan with Phospholipid Bilayers

Development of a CP 31P NMR Broadline Simulation Methodology for Studying the Interactions of Antihypertensive AT1 Antagonist Losartan with Phospholipid Bilayers

Strategies in the Rational Drug Design

Ligands, their receptors and … plasma membranes

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