Halogenation of Drugs Enhances Membrane Binding and Permeation (original) (raw)
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Link between Membrane Composition and Permeability to Drugs
Journal of chemical theory and computation, 2018
Prediction of membrane permeability to small molecules represents an important aspect of drug discovery. First-principles calculations of this quantity require an accurate description of both the thermodynamics and kinetics that underlie translocation of the permeant across the lipid bilayer. In this contribution, the membrane permeability to three drugs, or drug-like molecules, namely, 9-anthroic acid (ANA), 2',3'-dideoxyadenosine (DDA), and hydrocortisone (HYL), are estimated in a pure 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) and in a POPC:cholesterol (2:1) mixture. On the basis of independent 2-5-μs free-energy calculations combined with a time-fractional Smoluchowski determination of the diffusivity, the estimated membrane permeabilities to these chemically diverse permeants fall within an order of magnitude from the experimental values obtained in egg-lecithin bilayers, with the exception of HYL in pure POPC. This exception is particularly interesting because the ...
Biochimica Et Biophysica Acta - Biomembranes, 1986
Partition coefficients, kp, of chlorpromazine between the aqueous phase and lipid bilayer vesicles were determined as function of drug concentration, lipid chain length, cholesterol content and temperature encompassing the range of the lipid phase transition. Radioactivity and absorption measurements were performed to determine the kp values. Up to a concentration of 3. l0-s M, the partition coefficient is independent of chlorpromazine concentration, whereas it decreases drastically at higher chlorpromazine concentrations, at which membrane lysis is observed. Membrane structure is not disturbed at less than 3.10-s M chlorpromazine, as was concluded from electron paramagnetic resonance studies measuring TEMPO partitioning and order degree. However, the lipid phase-transition temperature decreases and is broadened at higher chlorpromazine concentrations. From fluorescence measurements, we conclude the formation of chlorpromazine micelles at concentrations higher than 5-l0-5 M in chlorpromazine in the absence of lipids and the formation of mixed micelles in the presence of lipids. The effect of lipid chain length on kp values was investigated. The partition coefficient decreases from 8100 in dilauroyi-to 3400 in dipalmitoylphosphatidyicholine vesicles, both at 50°C, that is, above their corresponding phase-transition temperature t t. At t < t t the kp values are strongly reduced, by at least a factor of 10, depending on lipid chain length and membrane composition. It is possible to establish a lipid phase-transition curve from the temperature-dependent measurements of the kp values. Cholesterol within the lipid membrane strongly decreases kp. At 20 mol% cholesterol in dipalmitoylphosphatidylcholine membranes, the partition coefficient is reduced from 3400 to 2300. This value is well comparable to the kp value obtained in erythrocyte ghosts. In contradiction to earlier experiments by Conrad and Singer (Biochemistry 20 (1981) 808-818), this value in a biological membrane could be obtained by the hygroscopic desorption as well as the centrifugation method. From our experiments we are justified in further considering artificial bilayer membranes as models for biological membranes.
Biochimica Et Biophysica Acta-biomembranes, 2000
We have employed four lipids in the present study, of which two are cationic and two bear phosphatidylcholine (PC) headgroups. Unlike dipalmitoylphosphatidylcholine, the other lipids employed herein do not have any ester linkage between the hydrocarbon chains and the respective lipid backbones. Small unilamellar vesicles formed from each of the PC and cationic lipids with or without varying amounts of cholesterol have been examined using the steady-state fluorescence anisotropy method as a function of temperature. The anisotropy data clearly indicate that the order in the lipid bilayer packing is strongly affected upon inclusion of cholesterol. This effect is similar irrespective of the electrostatic character of the lipid employed. The influence of cholesterol inclusion on multi-lamellar lipid dispersions has also been examined by 1 Hnuclear magnetic resonance spectroscopy above the phase transition temperatures. With all the lipids, the line widths of (CH 2 ) n protons of hydrocarbon chains in the NMR spectra respond to the addition of cholesterol to membranes. The influence on the bilayer widths of various lipids upon inclusion of cholesterol was determined from X-ray diffraction studies of the cast films of the lipid^cholesterol coaggregates in water. The effect of cholesterol on the efflux rates of entrapped carboxyfluorescein (CF) from the phospholipid vesicles was determined. Upon incremental incorporation of cholesterol into the phospholipid vesicles, the CF leakage rates were progressively reduced. Independent experiments measuring transmembrane OH 3 ion permeation rates from cholesterol-doped cationic lipid vesicles using entrapped dye riboflavin also demonstrated that the addition of cholesterol into the cationic lipid vesicles reduced the leakage rates irrespective of lipid molecular structure. It was found that the cholesterol induced changes on the membrane properties such as lipid order, linewidth broadening, efflux rates, bilayer widths, etc., did not depend on the ability of the lipids to participate in the hydrogen bonding interactions with the 3L-OH of cholesterol. These findings emphasize the importance of hydrophobic interaction between lipid and cholesterol and demonstrate that it is not necessary to explain the observed cholesterol induced effects on the basis of the presence of hydrogen bonding between the 3L-OH of cholesterol and the lipid chain^backbone linkage region or headgroup region. ß
Structural Determinants of Water Permeability through the Lipid Membrane
The Journal of General Physiology, 2007
Despite intense study over many years, the mechanisms by which water and small nonelectrolytes cross lipid bilayers remain unclear. While prior studies of permeability through membranes have focused on solute characteristics, such as size, polarity, and partition coeffi cient in hydrophobic solvent, we focus here on water permeability in seven single component bilayers composed of different lipids, fi ve with phosphatidylcholine headgroups and different chain lengths and unsaturation, one with a phosphatidylserine headgroup, and one with a phosphatidylethanolamine headgroup. We fi nd that water permeability correlates most strongly with the area/lipid and is poorly correlated with bilayer thickness and other previously determined structural and mechanical properties of these single component bilayers. These results suggest a new model for permeability that is developed in the accompanying theoretical paper in which the area occupied by the lipid is the major determinant and the hydrocarbon thickness is a secondary determinant. Cholesterol was also incorporated into DOPC bilayers and X-ray diffuse scattering was used to determine quantitative structure with the result that the area occupied by DOPC in the membrane decreases while bilayer thickness increases in a correlated way because lipid volume does not change. The water permeability decreases with added cholesterol and it correlates in a different way from pure lipids with area per lipid, bilayer thickness, and also with area compressibility.
Structural Determinants of Drug Partitioning in Surrogates of Phosphatidylcholine Bilayer Strata
Molecular Pharmaceutics, 2013
Surrogate phases have been widely used as correlates for modeling transport and partitioning of drugs in biological systems, taking advantage of chemical similarity between the surrogate and the phospholipid bilayer as the elementary unit of biological phases, which is responsible for most of transport and partitioning. Solvation in strata of the phospholipid bilayer is an important drug characteristics because it affects the rates of absorption and distribution, as well as the interactions with the membrane proteins having the binding sites located inside the bilayer. The bilayer core can be emulated by n-hexadecane (C16), and the headgroup stratum is often considered a hydrophilic phase because of the high water content. Therefore, we tested the hypothesis that the C16/water partition coefficients (P) can predict the bilayer locations of drugs and other small molecules better than other surrogate systems. Altogether 514 P C16/W values for nonionizable (458) and completely ionized (56) compounds were collected from the literature or measured, when necessary. With the intent to create a fragment-based prediction system, the P C16/W values were factorized into the fragment solvation parameters (f) and correction factors based on the ClogP fragmentation scheme. A script for the P C16/W prediction using the ClogP output is provided. To further expand the prediction system and reveal solvation differences, the f C16/W values were correlated with their more widely available counterparts for the 1octanol/water system (O/W) using solvatochromic parameters. The analysis for 50 compounds with known bilayer location shows that the available and predicted P C16/W and P O/W values alone or the P C16/O values representing their ratio do not satisfactorily predict the preference for drug accumulation in bilayer strata. These observations indicate that the headgroups stratum, albeit well hydrated, does not have solvation characteristics similar to water and is also poorly described by the O/W partition characteristics. by 1 H NMR data 7 and molecular dynamics simulations. 10 In this way, wet 1-octanol imitates, to some extent, overall partitioning of drugs between phospholipid bilayers and surrounding water.
Interactions of cholesterol with the membrane lipid matrix. A solid state NMR approach
Biochimie, 1991
The effects of cholesterol on the structure and dynamics of dimyristoylphosphatidylcholine (DMPC) model membranes have been monitored as functions of temperature and cholesterol concentration in the membrane. The use of deuterium labels both on the cholesterol fused ring system and on the lipid chains in conjunction with solid state deuterium nuclear magnetic resonance (2H-NMR) afforded to monitor the degree of ordering of both molecules in a mixed system. The degree of ordering of the lipid head group was followed by phosphorus-31 (31p)-NMR. New findings on the effect of cholesterol on DMPC may be summarized as follows: i) cholesterol disorders the lipid chains below temperature of the DMPC gel-to-fluid transition (To) and orders them above; the effect is linear with cholesterol concentration at 0 and 60°C but for intermediate temperatures, a saturation effect is observed at 20-30 mol %; ii) the ordering-disordering effects are perceived similarly by all chain segments with, however, a greater sensitivity for positions near the bilayer center; iii) below To, the lipid head group is considerabily disordered by increasing amounts of cholesterol but slightly affected above; iv) the degree of ordering of cholesterol is quasi temperature independent for fractions greater than or equal to 30%; v) the average orientation of the cholesterol rigid body is perpendicular to the bilayer surface and exhibits little variations with temperature and cholesterol concentration. Variations in membrane dynamics are interpreted in terms of cholesterol-induced changes in bilayer thickness. The sterol is described as a regulator of membrane dynamics (for fractions greater than or equal to 30%) by providing the bilayer with quasi constant motional amplitudes over a large temperature scale.