In Silico Prediction of Physicochemical Properties

This report provides a critical review of computational models, and in particular(quantitative) structure-property relationship (QSPR) models, that are available for the prediction of physicochemical properties. The emphasis of the review is on the usefulness of the models for the regulatory assessment of chemicals, particularly for the purposes of the new European legislation for the Registration, Evaluation, Authorisation and Restriction of CHemicals (REACH), which entered into force in the European Union (EU) on 1 June 2007. It is estimated that some 30,000 chemicals will need to be further assessed under REACH. Clearly, the cost of determining the toxicological and ecotoxicological effects, the distribution and fate of 30,000 chemicals would be enormous. However, the legislation makes it clear that testing need not be carried out if adequate data can be obtained through information exchange between manufacturers, from in vitro testing, and from in silico predictions. The effects of a chemical on a living organism or on its distribution in the environment is controlled by the physicochemical properties of the chemical. Important physicochemical properties in this respect are, for example, partition coefficient, aqueous solubility, vapour pressure and dissociation constant. Whilst all of these properties can be measured, it is much quicker and cheaper, and in many cases just as accurate, to calculate them by using dedicated software packages or by using (QSPRs). These in silico approaches are critically reviewed in this report.JRC.I.3-Toxicology and chemical substance

Prediction of Partition Coefficients and Permeability of Drug Molecules in Biological Systems with Abraham Model Solute Descriptors Derived from Measured Solubilities and Water-to-Organic Solvent Partition Coefficients

Book chapter on the prediction of partition coefficients and permeability of drug molecules in biological systems with Abraham model solute descriptors derived from measured solubilities and water-to-organic solvent partition coefficients

Prediction of partition coefficients for systems of micelles using DFT

[eng] A compound’s solvent−water partition coefficient (log P) measures the equilibrium ratio of the compound’s concentrations in a two-phase system: as two solvents in contact or a system of micelles in an aqueous solution. In this thesis, the partition coefficient of three groups of small compounds (alcohol, ether, and hydrocarbons) in 10 different solvents (benzene, cyclohexane, hexane, n-Octane, toluene, carbon tetrachloride, heptane, trichloroethane, and octanol) was computed used DFT and B3LYP method with 6.31G(d), 6.311+G** and 6.311++G** basis sets. It is obtained that the partition coefficient of alcohol solutes in various solvents using the 6.31G(d) basis set indicates a satisfactory correlation with experimental values. The correlation between the experimental value and the partition coefficient of ether solutes in different solvents using the 6.311++G** basis set shows high agreement. The experimental data displayed a high correlation with the partition coefficient computed for hydrocarbon compounds in various solvents using all three basis sets: 6.31G(d), 6.311+G**, and 6.311++G**. In addition, we have studied the correlation of the experimental partition coefficients in Sodium Dodecyl Sulfate (SDS), Hexadecyltrimethylammonium bromide (HTAB), Sodium cholate (SC), and Lithium perfluoro octane sulfonate (LPFOS) micelles with ab initio calculated partition coefficients in 15 different organic solvents. Specifically, the partition coefficients of a series of 63 molecules in an aqueous system of SDS, SC, HTAB, and LPFOS micelles are correlated with the partition coefficient in heptane/water, cyclohexane/water, n-dodecane/water, pyridine/water, acetic acid/water, octanol/water, acetone/water, 1-propanol/water, 2-propanol/water, methanol/water, formic acid/water, diethyl sulfide/water, decan-1-ol/water, 1-2 ethane diol/water and dimethyl sulfoxide/water systems. All calculations were performed using the Gaussian 16 Quantum Chemistry package. Molecular structures were generated in the more extended conformation using Avogadro, and geometries of all molecules were optimized using Density Functional Theory (DFT) B3LYP and MO6-2X with 6-31++G** basis set by the continuum solvation model based on density (SMD). The obtained results show that calculated partition coefficients in the alcohol/water mixture give the best correlation to predict the experimental partition coefficients in SDS, SC, and LPFOS micelles. With respect to HTAB micelle systems, a new selection of molecules is created, excluding those containing N atoms and Urea atom groups. Interestingly, the partition coefficient of these chosen molecules exhibits a strong correlation with the experimental partition coefficient. Finally, the partition coefficient of flexible molecules was studied by the same protocol for two solvent combinations, octanol/water and cyclohexane/water. The calculated values were compared with the experimental partition coefficients. The average partition coefficient in octanol solvent exhibited a high correlation with the experimental data. However, for the 16 compounds in the cyclohexane solvent, their partition coefficients do not exhibit significant agreement with the experimental partition coefficients.[cat] S'ha desenvolupat una metodologia computacional per calcular el coeficient de partició de diferents tipus de molècules en sistemes micel·lars. En primer lloc, s'ha calculat el coeficient de partició de tres grups de compostos (alcohol, èter i hidrocarburs) utilitzant el mètode DFT amb el funcional B3LYP. S'han obtingut correlacions satisfactòries amb els valors experimentals. En aquesta tesi s'ha desenvolupat un procediment per calcular els coeficients de partició experimentals en micel·les de dodecilsulfat de sodi (SDS), bromur d'hexadeciltrimetilamoni (HTAB), colat de sodi (SC) i perfluorooctanosulfonat de liti (LPFOS). Específicament, els coeficients de partició d'una sèrie de 63 molècules en un sistema aquós de micel·les de SDS, SC, HTAB i LPFOS es correlacionen amb el coeficient de partició en deu barreges aquoses. Els resultats obtinguts mostren que els coeficients de partició calculats a la barreja alcohol/aigua donen la millor correlació per predir els coeficients de partició experimentals en micel·les SDS, SC i LPFOS. Pel que fa als sistemes micelars HTAB, es crea una nova selecció de molècules, excloent-ne aquelles que contenen àtoms de N aromàtics i grups d'urea. És interessant notar que el coeficient de partició d'aquestes molècules triades mostra una forta correlació amb el coeficient de partició experimental. Finalment, es va estudiar el coeficient de partició de molècules flexibles mitjançant el mateix protocol per a dues combinacions de dissolvents, octanol/aigua i ciclohexà/aigua. Els valors calculats es van comparar amb els coeficients de partició experimentals. El coeficient de partició mitjana en dissolvent octanol va mostrar una alta correlació amb les dades experimentals. Tot i això, per als 16 compostos en el dissolvent ciclohexà, els seus coeficients de partició no mostren una concordança significativa amb els coeficients de partició experimental

Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations.

Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state) or translocation rates and therefore potency to bind to different sites in membrane proteins. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity. As a proof of principle, we evaluated extensively lipid membrane partitioning of d-sotalol, well-known blocker of a cardiac potassium channel Kv11.1 encoded by the hERG gene, with reported substantial proclivity for arrhythmogenesis. We developed the positively charged (cationic) and neutral d-sotalol models, compatible with the biomolecular CHARMM force field, and subjected them to all-atom molecular dynamics (MD) simulations of drug partitioning through hydrated lipid membranes, aiming to elucidate thermodynamics and kinetics of their translocation and thus putative propensities for hydrophobic and aqueous hERG access. We found that only a neutral form of d-sotalol accumulates in the membrane interior and can move across the bilayer within millisecond time scale, and can be relevant to a lipophilic channel access. The computed water-membrane partitioning coefficient for this form is in good agreement with experiment. There is a large energetic barrier for a cationic form of the drug, dominant in water, to cross the membrane, resulting in slow membrane translocation kinetics. However, this form of the drug can be important for an aqueous access pathway through the intracellular gate of hERG. This route will likely occur after a neutral form of a drug crosses the membrane and subsequently re-protonates. Our study serves to demonstrate a first step toward a framework for multi-scale in silico safety pharmacology, and identifies some of the challenges that lie therein