Hg-supported phospholipid monolayer as rapid screening device for low molecular weight narcotic compounds in water.

This study positions the fabricated Pt/Hg-supported phospholipid sensor element in the context of more conventional biomembrane-based screening platforms. The technology has been used together with immobilised artificial membrane (IAM) chromatography and COSMOmic simulation methods to screen the interaction of a series of low molecular weight narcotic organic compounds in water with phosphatidylcholine (PC) membranes. For these chemicals it is shown that toxicity to aquatic species is related to compound hydrophobicity which is associated with compound accumulation in the phospholipid membrane as modelled by IAM chromatography measurements and COSMOmic simulations. In contrast, the Hg-supported dioleoyl phosphatidylcholine (DOPC) sensor element records membrane damage/modification which is indirectly related to general toxicity and directly related to compound structure. Electrochemical limit of detection (LoD) values depend on molecular structure and range from 20 µmolL-1 for substituted phenols to 23 mmolL-1 for aliphatics. Rapid cyclic voltammetry (RCV) "fingerprints" showed that the major structural classes of compounds: alkyl/chlorobenzenes, substituted phenols, quaternary ammonium compounds and neutral amines interacted distinctively with the DOPC on Hg and that these observations correlated with and supported those predicted by the COSMOmic simulations of the compound/DMPC association. In addition, the compatibility of the electrochemical and COSMOmic methods validates the electrochemical device as a meaningful high throughput technology to screen compounds in water and report on the mechanistic details of their interaction with phospholipid layers.

Diffusion of energetic compounds through biological membrane: Application of classical MD and COSMOmic approximations.

Computational studies of the potential biological impact of several energetic compounds were performed. The most commonly used explosives were considered in the present studies: trinitrotoluene (TNT), 2,4-dinitrotoluene (2,4-DNT), 2,4-dinitroanisole (DNAN), and 5-Nitro-2,4-dihydro-3H-1,2,4-triazol-3-one (NTO). The effect of such factors as ionic strength and presence of DMSO in the water solution on the structure of the membrane were considered using the POPC lipid bilayer as an example. Molecular dynamics (MD) simulations revealed that, even on a short-time scale, the influence of those additives is noticeable, and therefore those factors should always be taken into account. The MD and the COSMOmic approaches were used to elucidate the ability of the energetic compounds to penetrate the living cell. Calculated free energy profiles and partitioning coefficients revealed distributions of the compounds in the lipid bilayer as well as an overall ability to enter the cell. MD in this case provides a better representation of the free energy profile, while the COSMOmic approach works better to predict log(Klipw) values. The effect of the functional group was observed for the profiles that were obtained using the MD method.

Accessing lipophilicity of drugs with biomimetic models: A comparative study using liposomes and micelles.

Lipophilicity is a physicochemical property of crucial importance in drug discovery and drug design. Biomimetic models, such as liposomes and micelles, constitute a valuable tool for the assessment of lipophilicity through the determination of partition coefficients (log Kp). However, the lack of standardization hampers the judgment about which model or method has the best and broadest passive drug permeation predictive capacity. This work provides a comparative analysis between the methodologies based on biomimetic models to determine the partition coefficient (log Kp). For that purpose, a set of reference substances preconized by the Organization for Economic Cooperation and Development (OECD) guidelines was used. The biomimetic models employed were liposomes and micelles composed by 1,2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC) and hexadecylphosphocholine (HePC), respectively. Both lipids were used as representative phospholipids of natural membranes. The partition coefficients between biomimetic models and aqueous phases were determined by derivative spectroscopy at physiological conditions (37 °C and pH 7.4). The partition coefficients obtained using biomimetic models are quite different and more reliable than the ones obtained using an octanol/water system. Comparing the performance of the two biomimetic models, micelles revealed to be suitable only for substances with high molar absorption coefficient and log Kp > 3, but in general liposomes are the best model for accessing lipophilicity of drugs. Furthermore, a comparison between experimental data and the partition coefficients determined by the computational method COSMOmic is also provided and discussed. As a final summarizing result, a decision tree is provided in order to guide the selection of a tool for assessing the lipophilicity of drugs.

Assessing the toxicity of ionic liquids - Application of the critical membrane concentration approach.

Charged organic chemicals are a prevailing challenge for toxicity modelling. In this contribution we strive to recapitulate the lessons learned from the well-known modelling of narcosis (or baseline toxicity) of neutral chemicals and apply the concept to charged chemicals. First we reevaluate the organism- and chemical independent critical membrane concentration causing 50% mortality,.cmemtox, based on a critical revision of a previously published toxicity dataset for neutral chemicals. In accordance to values reported in the literature we find a mean value for cmemtox of roughly 100 mmol/kg (membrane lipid) for a broad variety of 42 aquatic organisms (333 different chemicals), albeit with a considerable scatter. Then we apply this concept to permanently charged ionic liquids (ILs). Using COSMOmic, a quantum mechanically based mechanistic model that makes use of the COSMO-RS theory, we predict membrane-water partition coefficients (Kmem/w) of the anionic and cationic IL components. Doing so, cmemtox(total) for permanently charged ILs can be estimated assuming independent, concentration additive contributions of the cationic and its respective anionic species. The resulting values for some of the toxicity data for ionic liquids are consistent with the expected range for baseline toxicity for neutral chemicals while other values are consistently greater or smaller. Based on the calculation of toxic ratios we identify ILs that exert a specific mode of toxic action. Limitations of the modelling approach especially but not exclusively due to the use of nominal concentrations instead of freely-dissolved concentrations in the published literature are critically discussed.

Comparison of different models predicting the phospholipid-membrane water partition coefficients of charged compounds.

A large fraction of commercially used chemicals is ionizable. This results in the need for mechanistic models to describe the physicochemical properties of ions, like the membrane-water partition coefficient (K(mw)), which is related to toxicity and bioaccumulation. In this work we compare 3 different and already existing modelling approaches to describe the liposome-water partition coefficient (K(lipw)) of organic ions, including 36 cations, 56 anions, 2 divalent cations and 2 zwitterions (plus 207 neutral compounds for ensuring model consistency). 1) The empirical correlation with the octanol-water partition coefficient of the corresponding neutral species yielded better results for the prediction of anions (RMSE = 0.79) than for cations (RMSE = 1.14). Though describing most anions reasonably well, the lack of mechanistic basis and the poor performance for cations constrain the usage of this model. 2) The polyparameter linear free energy relationship (pp-LFER) model performs worse (RMSE = 1.26/1.12 for anions/cations). The different physicochemical environments, due to different sorption depths into the membrane of the different species, cannot be described with a single pp-LFER model. 3) COSMOmic is based on quantum chemistry and fluid phase thermodynamics and has the widest applicability domain. It was the only model applicable for multiply charged ions and gave the best results for anions (RMSE = 0.66) and cations (RMSE = 0.71). We expect COSMOmic to contribute to a better estimation of the environmental risk of ionizable emerging pollutants.