Interaction of Lovastatin with Model Membranes by NMR Data and from MD Simulations

Shurshalova, G. S.; Yulmetov, Aydar; Sharapova, Diana A.; Аганов, А. В.; Клочков, В. В.

doi:10.1007/s12668-020-00722-4

Cited by 7 publications

(7 citation statements)

References 31 publications

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“…However, its application to molecules-cell membranes interaction studies may be difficult, because relaxation times for phospholipid aggregates are too large compared with the NMR chemical shift time scale. [40][41][42][43][44] Therefore, the hydrophobic environment of a bacterial membrane was simulated by sodium dodecylsulfate (SDS), one of the most widely used surfactants for the membrane modeling in NMR field. [45][46][47][48][49][50] Indeed, the SDS micelles have a larger correlation time with respect to the NMR time-scale and their small size allows a good spectral resolution.…”

Section: Nmr Spectroscopymentioning

confidence: 99%

Grapevine stilbenoids as natural food preservatives: calorimetric and spectroscopic insights into the interaction with model cell membranes

et al. 2021

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Section: Nmr Spectroscopymentioning

confidence: 99%

Grapevine stilbenoids as natural food preservatives: calorimetric and spectroscopic insights into the interaction with model cell membranes

et al. 2021

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“…The introduction of lovastatin in dodecyl phosphocholine (DPC) micelles is a simple model to mimic statin and biological membrane interactions. Using nuclear magnetic resonance (NMR), it was observed that lovastatin does not have a specific orientation within the lipid part of the micelle, albeit is fully embedded in the membrane [ 112 ]. On average, lovastatin is located within the hydrophobic, hydrocarbon tails in the non-polar inner part of DPC, but it is not possible to identify a specific position, which indicates a dynamic positioning of lovastatin [ 28 , 113 ] in the micelle.…”

Section: Interaction Of Statins With Membranesmentioning

confidence: 99%

“…On average, lovastatin is located within the hydrophobic, hydrocarbon tails in the non-polar inner part of DPC, but it is not possible to identify a specific position, which indicates a dynamic positioning of lovastatin [ 28 , 113 ] in the micelle. Further, it was determined that lovastatin penetrates the DPC hydrophobic tails with its butyryl and lactone ring deeper than its naphthalene ring structures, between 14 and 15 Å from the micelle centre of mass ( Figure 5 ) [ 112 ]. Similarly, in another study, it was observed that lovastatin, when bound to a planar, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer membrane, induced no effect on lipid packing, in spite of its dynamic orientation, and could not be accurately located, nor its orientation resolved [ 113 ].…”

Section: Interaction Of Statins With Membranesmentioning

confidence: 99%

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The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins

Murphy

Deplazes

Cranfield

et al. 2020

IJMS

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Statins are a class of drugs used to lower low-density lipoprotein cholesterol and are amongst the most prescribed medications worldwide. Most statins work as a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR), but statin intolerance from pleiotropic effects have been proposed to arise from non-specific binding due to poor enzyme-ligand sensitivity. Yet, research into the physicochemical properties of statins, and their interactions with off-target sites, has not progressed much over the past few decades. Here, we present a concise perspective on the role of statins in lowering serum cholesterol levels, and how their reported interactions with phospholipid membranes offer a crucial insight into the mechanism of some of the more commonly observed pleiotropic effects of statin administration. Lipophilicity, which governs hepatoselectivity, is directly related to the molecular structure of statins, which dictates interaction with and transport through membranes. The structure of statins is therefore a clinically important consideration in the treatment of hypercholesterolaemia. This review integrates the recent biophysical studies of statins with the literature on the physiological effects and provides new insights into the mechanistic cause of statin pleiotropy, and prospective means of understanding the cholesterol-independent effects of statins.

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“…4,13 It has been shown that lipophilic statins have a greater tendency to cause SAM than hydrophilic statins; also investigated in the PRIMO study above, 9 the hydrophilic statins (pravastatin and fluvastatin) were the least likely to cause muscle pain, while the most lipophilic statin tested, simvastatin (log P = 4.68), was most likely to cause muscular adverse effects. 14 Both experimental 10,15−21 and computational 19,21,22 studies of statin−lipid interactions have started to emerge, providing us with insight into the localization of these statins in membrane models and their impact on bilayer properties. In a recent solid-state NMR study, 20 pravastatin, a type 1 statin, caused the highest perturbation on membrane structure out of the statins investigated.…”

Section: Introductionmentioning

confidence: 99%

Modulation of Phospholipid Bilayer Properties by Simvastatin

Teo

Tieleman

2021

J. Phys. Chem. B

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Simvastatin (Zocor) is one of the most prescribed drugs for reducing high cholesterol. Although simvastatin is ingested in its inactive lactone form, it is converted to its active dihydroxyheptanoate form by carboxylesterases in the liver. The dihydroxyheptanoate form can also be converted back to its original lactone form. Unfortunately, some of the side effects associated with the intake of simvastatin and other lipophilic statins at higher doses include statin-associated myopathy (SAM) and, in more severe cases, kidney failure. While the cause of SAM is unknown, it is hypothesized that these side effects are dependent on the localization of statins in lipid bilayers and their impact on bilayer properties. In this work, we carry out all-atom molecular dynamics simulations on both the lactone and dihydroxyheptanoate forms of simvastatin (termed "SN" and "SA", respectively) with a pure 1-palmitoyl-2oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer and a POPC/cholesterol (30 mol %) binary mixture as membrane models. Additional simulations were carried out with multiple simvastatin molecules to mimic in vitro conditions that produced pleiotropic effects. Both SN and SA spontaneously diffused into the lipid bilayer, and a longer simulation time of 4 μs was needed for the complete incorporation of multiple SAs into the bilayer. By constructing potential mean force and electron density profiles, we find that SN localizes deeper within the hydrophobic interior of the bilayer and that SA has a greater tendency to form hydrogen-bonding interactions with neighboring water molecules and lipid headgroups. For the pure POPC bilayer, both SN and SA increase membrane order, while membrane fluidity increases for the POPC/cholesterol bilayer.

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Interaction of Lovastatin with Model Membranes by NMR Data and from MD Simulations

Cited by 7 publications

References 31 publications

Grapevine stilbenoids as natural food preservatives: calorimetric and spectroscopic insights into the interaction with model cell membranes

Grapevine stilbenoids as natural food preservatives: calorimetric and spectroscopic insights into the interaction with model cell membranes

The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins

Modulation of Phospholipid Bilayer Properties by Simvastatin

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