Interaction of different statins with model membranes by NMR data

Abstract

Hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins reduce the amount of low-density lipoprotein (LDL) cholesterol, which is known as a well-established risk factor for atherosclerosis. Despite the fact that statins have a common pharmacologic target essential to sterol biosynthesis, their efficacy, safety, and potential non-LDL actions vary significantly for different statins. There is a hypothesis that pharmacological features of statins depend on their location in cell membrane, but to the present day there is a lack of information in literature on interactions of statins with the surface of the cell membrane in liquid media. The results of NMR experiments showed that all studied statins form intermolecular complexes with models of cell membranes (dodecylphosphocholine micelles) in water solution. Locations of pravastatin, simvastatin, fluvastatin and cerivastatin on model membranes were established by NOESY NMR data. Distinctions in their positions can explain differences in pharmacological properties of studied compounds.

Drug orientations within statin-loaded lipoprotein nanoparticles by 19F solid-state NMR

“…If the chemical shift tensor orientation relative to the molecular geometry is known, one can relate the measured chemical shift anisotropy to the average orientation of the drug in the lipid bilayer. DFT calculations predict that the 19 F chemical shift tensor is oriented with the least-shielded component d 11 exactly in plane with the aromatic ring and d 22 directed along the fluorine-carbon bond (Fig. S1, ESI †), as seen for other fluorophenyl compounds.…”

“…Here we use 19 F NMR as a sensitive probe of the molecular orientations of fluorine-containing drugs as they undergo anisotropic motion within a reconstituted high-density lipoprotein (rHDL) nanoparticle formulation. rHDL nanoparticles are attractive drug delivery vehicles that are well-tolerated in vivo, do not invoke an immune response and are capable of delivering lipophilic drugs to tissues via specific receptors.…”

“…9 A drug's orientation within the rHDL lipid matrix will influence how the drug is presented to a receptor and so may affect the rate and selectivity of transfer. 10 We exploit 19 F chemical shifts and 1 H- 19 F dipolar couplings 11 to compare the orientations of two lipophilic fluoroaromatic drugs within the lipid bilayer component of rHDL particles. We chose as our drugs two fluorine-bearing statins, fluvastatin (log P = 4.17) and rosuvastatin (log P = 1.47) (Scheme 1); statinloaded rHDL nanoparticles have been shown to reduce atherosclerotic lesions in an atherosclerosis mouse model.…”

Statins and Their Interaction With Model Cell Membranes According to the Data of Nuclear Magnetic Resonance Spectroscopy

“…Мицеллы додецилфосфохолина представляют собой сфериче-ские агрегаты, распределенные по всему раствору, имеют полярную поверхность, аналогичную поверхности клеточных мембран и являются наиболее подходящей модельной системой с точки зрения метода ЯМР из-за их небольших размеров. Ранее нами было показано, что правастатин, симвастатин, церивастатин и флувастатин образуют комплексы с мицеллами ДФХ [12,13]. Целью данной работы стало изучение пространственного рас-положения вышеуказанных статинов относительно по-верхности модельных клеточных мембран, а также оцен-ка средних межатомных расстояний между молекула-ми статинов и мицелл ДФХ.…”

“…В работе [13] нами было определено расположение статинов в модельной клеточной мембране на каче-ственном уровне. В 2D NOESY спектрах флувастатина, кросс-пики в которых соответствуют близкому про-странственному расположению соответствующих групп атомов, наблюдались кросс-пики между сигналами циклической части молекулы флувастатина (2',3',5',6',11-14) и B, C, D, F, H сигналами додецил-фосфохолина.…”