Structural Determinants of Drug Partitioning in Surrogates of Phosphatidylcholine Bilayer Strata (original) (raw)
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Molecular Pharmaceutics, 2014
Solvation of drugs in the core (C) and headgroup (H) strata of phospholipid bilayers affects their physiological transport rates and accumulation. These characteristics, especially a complete drug distribution profile across the bilayer strata, are tedious to obtain experimentally, to the point that even simplified preferred locations are only available for a few dozen compounds. Recently, we showed that the partition coefficient (P) values in the system of hydrated diacetyl phosphatidylcholine (DAcPC) and nhexadecane (C16), as surrogates of the Hand C-strata of the bilayer composed of the most abundant mammalian phospholipid, PC, agree well with the preferred bilayer location of compounds. High P values are typical for lipophiles accumulating in the core, and low P values are characteristic of cephalophiles preferring the headgroups. This simple pattern does not hold for most compounds, which usually have more even distribution and may also accumulate at the H/C interface. To model complete distribution, the correlates of solvation energies are needed for each drug state in the bilayer: (1) for the Hstratum it is the DAcPC/W P value, calculated as the ratio of the C16/W and C16/DAcPC (W for water) P values; (2) for the C-stratum, the C16/W P value; (3) for the H/C interface, the P values for all plausible molecular poses are characterized using the fragment DAcPC/W and C16/W solvation parameters for the parts of the molecule embedded in the Hand C-strata, respectively. The correlates, each scaled by two Collander coefficients, were used in a nonlinear, mass-balance based model of intrabilayer distribution, which was applied to the easily measurable overall P values of compounds in the DMPC (M = myristoyl) bilayers and monolayers as the dependent variables. The calibrated model for 107 neutral compounds explains 94% of experimental variance, achieves similar cross-validation levels, and agrees well with the nontrivial, experimentally determined bilayer locations for 27 compounds. The resulting structure-based prediction system for intrabilayer distribution will facilitate more realistic modeling of passive transport and drug interactions with those integral membrane proteins, which have the binding sites located in the bilayer, such as some enzymes, influx and efflux transporters, and receptors. If only overall bilayer accumulation is of interest, the 1-octanol/W P values suffice to model the studied set.
Structural Determinants of Drug Partitioning in n -Hexadecane/Water System
Journal of Chemical Information and Modeling, 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.
Langmuir, 2006
Solvation free energies of drugs, peptides, and other small molecules in the core and headgroup regions of phospholipid bilayers determine their conformations, accumulation, and transport properties. The transfer free energy includes the energy terms for the formation of a cavity for the solute, the interactions of the solute with phospholipids, electrostatic interactions of the solute with the membrane and dipole potentials, and entropy terms. The interaction energies with phospholipids can be estimated by correlating the partitioning in surrogate solvent systems and in the bilayer. As the headgroup surrogate, we use diacetylphosphatidylcholine (DAcPC), the acetylated headgroup of the most abundant mammalian phospholipid, phosphatidylcholine, which forms a homogeneous solution with acceptable viscosity, when mixed with water in ratios similar to those in the fully hydrated bilayer. The two-phase system of n-hexadecane (C16) as the core surrogate and hydrated DAcPC was used to monitor partitioning of sixteen nonionizable compounds. On the bilogarithmic scale, the C16/DAcPC partition coefficients correlate neither with those in the C16/water and 1octanol/water systems, nor with their difference, which is frequently used as a parameter of hydrogen bonding for prediction of the bilayer location of the solutes. The C16/DAcPC system provides a satisfactory emulation of the solvation properties of the bilayer regions, as reflected in correct predictions of the bilayer location for those of the studied chemicals, for which this information is available.
Molecular pharmaceutics, 2015
We used the solvatochromic correlation to explain the influence of characteristics of studied compounds on the partition coefficients (P) measured using n-hexadecane (C16) and the novel headgroup surrogate (diacetyl phosphatidylcholine, DAcPC), and compared them with those in other systems, including the C16/water (W) system. The comment analyzes why our correlation for the C16/W system has the standard deviation (SD) higher than that published previously. The main reason is that in our, much smaller, data set the measured P values are complemented by the P values predicted by a reliable, unrelated method. We believe that this approach is acceptable for the aforementioned comparison. We did not use just experimental values, as suggested in the comment, because the solvatochromic correlation, although exhibiting 35% reduction in the SD, was accompanied by a sign change of one of the regression coefficients. The recommended use of special solvatochromic solute characteristics for a fe...
Molecular Insight into Affinities of Drugs and Their Metabolites to Lipid Bilayers
The Journal of Physical Chemistry B, 2013
The penetration properties of drug-like molecules on human cell membranes are crucial for understanding the metabolism of xenobiotics and overall drug distribution in the human body. Here, we analyze partitioning of substrates of cytochrome P450s (caffeine, chlorzoxazone, coumarin, ibuprofen, and debrisoquine) and their metabolites (paraxanthine, 6hydroxychlorzoxazone, 7-hydroxycoumarin, 3-hydroxyibuprofen, and 4-hydroxydebrisoquine) on two model membranes: dioleoylphosphatidylcholine (DOPC) and palmitoyloleoylphophatidylglycerol (POPG). We calculated the free energy profiles of these molecules and the distribution coefficients on the model membranes. The drugs were usually located deeper in the membrane than the corresponding metabolites and also had a higher affinity to the membranes. Moreover, the behavior of the molecules on the membranes differed, as they seemed to have a higher affinity to the DOPC membrane than to POPG, implying they have different modes of action in human (mostly PC) and bacterial (mostly PG) cells. As the xenobiotics need to pass through lipid membranes on their way through the body and the effect of some drugs might depend on their accumulation on membranes, we believe that detailed information of penetration phenomenon is important for understanding the overall metabolism of xenobiotics.
Partition coefficients of drugs in bilayer lipid membranes
Experientia, 1993
The oil/water partition coefficient of drugs is widely accepted as a key parameter in drug design. The coefficients are usually determined using a bulk octanol phase to represent the lipid. The physiologically and pharmacologically relevant structure is, of course, the bilayer lipid membrane, but until now there has been no convenient means of measuring the partition coefficients of small molecules into a single bilayer. This paper demonstrates that the partition coefficient may be calculated from the change in membrane refractive index which occurs when a drug molecule partitions into the membrane. The refractive index is determined by an integratedoptics technique ideally suited to an ultra-thin structure such as a lipid bilayer.
European Journal of Pharmaceutical Sciences, 2004
The chromatographic capacity factors of 39 neutral and basic compounds were measured on an immobilized artificial membrane-phosphatidylcholine-drug discovery (IAM-PC-DD) HPLC column, and the values compared with both octanol/water partition coefficients and capacity factors previously obtained on an IAM-PC-MG column. These two columns differ in their lipidic phase, since the IAM-PC-MG phase is made of phosphatidylcholine as found in biomembranes, whereas the glycerol linker is absent in the IAM-PC-DD phase. We found that the two phases interact differently with basic compounds at different degrees of ionization. On the IAM-PC-MG column, ionized compounds are as strongly or more strongly retained than isolipophilic neutral compounds. In contrast, their retention on the IAM-PC-DD column is less strong than, or at most as strong as, that of isolipophilic neutral compounds. The IAM-PC-MG data appear as better predictors of the interactions between drugs and biological membranes. Indeed, they correlate better than the IAM-PC-DD data with partitioning in both biological membrane and liposomes; moreover, they are better correlated with biological activities from the literature. These results suggest that even modest modifications in the structure of IAM phospholipids can have a major effect on the retention of basic compounds. We conclude that an acceptable IAM-HPLC estimate of the interactions between biomembranes and basic compounds should rely on stationary phases that reproduce the structure of natural phospholipids.
European Journal of Pharmaceutical Sciences, 2012
The membrane phospholipid affinity data, log k IAM w , for 14 basic drugs spanning a wide lipophilicity range were measured by HPLC on two different phospholipid stationary phases, i.e. IAM.PC.MG and IAM.PC.DD2. These data related weakly with log P N values, the n-octanol/water partition coefficients of the neutral forms; poorer relationships were found with log D 7.0 values, the n-octanol/water partition coefficients of the mixtures of neutral and ionized forms at pH 7.0. The lack of collinearity confirms that, differently from partition in n-octanol/water, partition in phospholipids encodes not only lipophilic/hydrophobic intermolecular recognition forces but also ionic bonds, due to electrostatic interactions between electrically charged species and phospholipids, according to the ''pH-piston hypothesis''. This component of interaction was parameterized by D log k IAM w values; they are the differences between the log k IAM w values experimentally measured and the values expected for neutral isolipophilic compounds. D log k IAM w values of the various analytes changed almost linearly from positive to negative values at increasing lipophilicity. This behavior is consistent with an interaction mechanism with membrane phospholipids including two intermolecular interaction forces: (i) lipophilic/hydrophobic interactions, which decrease on ionization proportionally to the lipophilicity of the neutral forms, and (ii) electrostatic interactions, which increase on ionization and are quite constant for all the analytes at a given ionization degree. Since BBB passage of the considered compounds is supposed to be based on passive mechanisms, we investigated the possible relationships between log BB values, i.e. the logarithms of the ratio between brain and blood concentrations, and three physico-chemical parameters, i.e. (i) log P N (lipophilic interaction of the neutral form), (ii) log k IAM w (global interaction with phospholipids), and (iii) D log k IAM w (electrostatic component of interaction with phospholipids). The results suggest that the electrostatic interactions encoded in log k IAM w values might act as trapping forces in a phospholipid barrier. Actually, we observed an inverse linear dependence of log BB on D log k IAM w values, but only for the compounds showing positive D log k IAM w
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 ...
The Journal of Physical Chemistry B, 2011
The interactions of the antihypertensive AT 1 antagonists candesartan and losartan with membrane bilayers were studied through the application of DSC, Raman, and solid state 31 P NMR spectroscopies. 1 H and 13 C NMR resonances of candesartan were assigned on the basis of 1D and 2D NMR spectroscopy. A 31 P CP NMR broadline fitting methodology in combination with ab initio computations was implemented and, in conjunction with DSC and Raman results, provided valuable information regarding the perturbation, localization, orientation, and dynamic properties of the drugs in membrane models. In particular, results indicate that losartan anchors in the mesophase region of the lipid bilayers with the tetrazole group oriented toward the polar headgroup, whereas candesartan has less definite localization spanning from water interface toward the mesophase and upper segment of the hydrophobic region. Both sartan molecules decrease the mobilization of the phospholipids alkyl chains. Losartan exerts stronger interactions compared with candesartan, as depicted by the more prominent thermal, structural, and dipolar 1 HÀ 31 P changes that are caused in the lipid bilayers. At higher concentrations, candesartan strengthens the polar interactions and induces increased order at the bilayer surface. At the highest concentration used (20 mol %), only losartan induces formation of microdomains attributed to the flexibility of its alkyl chain. These results in correlation to reported data with other AT 1 antagonists strengthen the hypothesis that this class of molecules may approach the active site of the receptor by insertion in the lipid core, followed by lateral diffusion toward the binding site. Further, the similarities and differences of these drugs in their interactions with lipid bilayers establish, at least in part, their pharmacological properties. B dx.