COSMO<i>quick</i>: A Novel Interface for Fast σ‑Profile Composition and Its Application to COSMO-RS Solvent Screening Using Multiple Reference Solvents

We present a novel, simpler to use modification of the standard COSMO-RS solubility prediction scheme which in addition can achieve higher accuracy by the usage of multiple experimental reference solubilities. When only one reference solvent is used, the approach reduces to the original COSMO-RS-based solubility prediction. Considerable speedup and simplification compared to the original COSMO-RS arises from the usage of approximate σ-profiles generated from a database of COSMO-files from 65000 diverse molecules. This method enables fast and accurate solvent screening. Solubility predictions using the novel approach on pure solvents perform favorably when compared to NRTL-SAC calculations. The new method is accessible via a graphical user-interface (COSMO<i>quick</i>) and combines the reliability and broad applicability of COSMO-RS theory with some practical advantages of more empirical solubility models

Prediction of Solubilities and Partition Coefficients in Polymers Using COSMO-RS

Recent results concerning the prediction of thermodynamic properties of solutes in polymers are presented. In particular, the computation of vapor–liquid and gas–liquid equilibria (i.e., liquid and gas solubilities) in different polymers and partition coefficients between the polymer and a solvent phase are addressed. Calculations have been carried out using COSMO-RS theory which combines quantum-chemical calculations with efficient statistical thermodynamics for intermolecular interactions. Predictions for vapor–liquid equilibria and for partition coefficients have been improved by incorporation of polymer-specific entropic contributions due to free volume effects. It is demonstrated that a high predictive accuracy is obtained if the polymer is sufficiently characterized by its composition, density, and crystallinity. The approach is currently limited to gaseous and liquid solutes and to linear, i.e. non-cross-linked polymers without any significant swelling

Predicting Flash Points of Pure Compounds and Mixtures with COSMO-RS

Flash point (FP) is an important parameter for assessing the safety of chemical compounds. Many empirical approaches have been developed to predict FPs based on molecular structure, sometimes involving a large number of descriptors and resulting in class-specific equations. We demonstrate in this work that a satisfying and rather general prediction of the saturation pressure at the FP can be achieved using only the molecular surface area. This relation in combination with any experimental or computational method for calculating temperature-dependent vapor pressures thus allows for the prediction of the FP. In a second step, we calculate the FPs of mixtures using COSMO-RS activity coefficients. By using the proposed method, we were able to calculate flash points without the need for data typically generated in experiments such as normal boiling points or enthalpies of combustion, although experimental pure-compound FPs and vapor-pressure data still can be used to increase the prediction quality

Prediction of Blood-Βrain Partitioning and Human Serum Albumin Binding Based on COSMO-RS σ-Moments

Models for the prediction of blood-brain partitioning (logBB) and human serum albumin binding (logK(HSA)) of neutral molecules were developed using the set of 5 COSMO-RS σ-moments as descriptors. These σ-moments have already been introduced earlier as a general descriptor set for partition coefficients. They are obtained from quantum chemical calculations using the continuum solvation model COSMO and a subsequent statistical decomposition of the resulting polarization charge densities. The model for blood-brain partitioning was built on a data set of 103 compounds and yielded a correlation coefficient of r2 = 0.71 and an rms error of 0.40 log units. The human serum albumin binding model was built on a data set of 92 compounds and achieved an r2 of 0.67 and an rms error of 0.33 log units. Both models were validated by leave-one-out cross-validation tests, which resulted in q2 = 0.68 and a qms error of 0.42 for the logBB model and in q2 = 0.63 and a qms error of 0.35 for the logK(HSA) model. Together with the previously published models for intestinal absorption and for drug solubility the presented two models complete the COSMO-RS based set of ADME prediction models

COSMO<i>sim3D</i>: 3D-Similarity and Alignment Based on COSMO Polarization Charge Densities

COSMO σ-surfaces resulting from quantum chemical calculations of molecules in a simulated conductor, and their histograms, the so-called σ-profiles, are widely proven to provide a very suitable and almost complete basis for the description of molecular interactions in condensed systems. The COSMO<i>sim</i> method therefore introduced a global measure of molecular similarity on the basis of similarity of σ-profiles, but it had the disadvantage of neglecting the 3D distribution of molecular polarities, which is crucially determining all ligand–receptor binding. This disadvantage is now overcome by COSMO<i>sim3D</i>, which is a logical and physically sound extension of the COSMO<i>sim</i> method, which uses local σ-profiles on a spatial grid. This new method is used to measure intermolecular similarities on the basis of the 3D representation of the surface polarization charge densities σ of the target and the probe molecule. The probe molecule is translated and rotated in space in order to maximize the sum of local σ-profile similarities between target and probe. This sum, the COSMO<i>sim3D</i> similarity, is a powerful descriptor of ligand similarity and allows for a good discrimination between bioisosters and random pairs. Validation experiments using about 600 pharmacological activity classes in the MDDR database are given. Furthermore, COSMO<i>sim3D</i> represents a unique and very robust method for a field-based ligand–ligand alignment

Comment on the Correct Use of Continuum Solvent Models

Comment on the Correct Use of Continuum Solvent Model

Thermochemistry of Chlorobenzenes and Chlorophenols: Ambient Temperature Vapor Pressures and Enthalpies of Phase Transitions

This work has been undertaken in order to obtain additional data on vapor pressures of chlorobenzene derivatives and to develop the group-additivity values necessary for predicting their vaporization enthalpies at the reference temperature T = 298.15 K. Molar enthalpies of sublimation and of vaporization of hexachlorobenzene and of mono-, di-, tri-, and pentachlorophenol were obtained from the temperature dependence of the vapor pressure measured by the transpiration method. Thermochemical investigations of chlorobenzenes and chlorophenols available in the literature were collected and combined with our own experimental results to obtain their reliable standard molar enthalpies of vaporizaton at T = 298.15 K. The COSMO-RS procedure has been used for a priori prediction of the vapor pressures and vaporization enthalpies of the whole data set of chlorobenzenes and chlorophenols. The new results help to resolve uncertainties in the available thermochemical data on chlorobenzenes and chlorophenols studied

Thermochemistry of Chlorobenzenes and Chlorophenols: Ambient Temperature Vapor Pressures and Enthalpies of Phase Transitions

This work has been undertaken in order to obtain additional data on vapor pressures of chlorobenzene derivatives and to develop the group-additivity values necessary for predicting their vaporization enthalpies at the reference temperature T = 298.15 K. Molar enthalpies of sublimation and of vaporization of hexachlorobenzene and of mono-, di-, tri-, and pentachlorophenol were obtained from the temperature dependence of the vapor pressure measured by the transpiration method. Thermochemical investigations of chlorobenzenes and chlorophenols available in the literature were collected and combined with our own experimental results to obtain their reliable standard molar enthalpies of vaporizaton at T = 298.15 K. The COSMO-RS procedure has been used for a priori prediction of the vapor pressures and vaporization enthalpies of the whole data set of chlorobenzenes and chlorophenols. The new results help to resolve uncertainties in the available thermochemical data on chlorobenzenes and chlorophenols studied

COSMO<i>sar3D</i>: Molecular Field Analysis Based on Local COSMO σ‑Profiles

The COSMO surface polarization charge density σ resulting from quantum chemical calculations combined with a virtual conductor embedding has been widely proven to be a very suitable descriptor for the quantification of interactions of molecules in liquids. In a preceding paper, grid-based local histograms of σ have been introduced in the COSMO<i>sim3D</i> method, resulting in a novel 3D-molecular similarity measure and going along with a novel property-based molecular alignment method. In this paper, we introduce under the name COSMO<i>sar3D</i> the usage of the resulting array of local σ-profiles as a novel set of molecular interaction fields for 3D-QSAR, containing all information required for quantifying the virtual ligand–receptor interactions, including desolvation. In contrast to currently used molecular interaction fields, we provide a theoretical rationale that the logarithmic binding constants of ligands should be a linear function of the array of local σ-profiles. This makes them especially suitable for linear regression analysis methods such as PLS. We demonstrate that the usage of local σ-profiles in molecular field analysis inverts the role of ligands and receptor; while conventional 3D-QSAR considers the virtual receptor in potential energy fields provided by the ligands, our COSMO<i>sar3D</i> approach corresponds to the calculation of the free energy of the ligands in a virtual free energy field provided by the receptor. First applications of the COSMO<i>sar3D</i> method are presented, which demonstrate its ability to yield robust and predictive models that seem to be superior to the models generated on the basis of conventionally used molecular fields

First Principles Calculations of Aqueous p<i>K</i>_a Values for Organic and Inorganic Acids Using COSMO−RS Reveal an Inconsistency in the Slope of the p<i>K</i>_a Scale

The COSMO−RS method, a combination of the quantum chemical dielectric continuum solvation model COSMO with a statistical thermodynamics treatment for more realistic solvation (RS) simulations, has been used for the direct prediction of pKa constants of a large variety of 64 organic and inorganic acids. A highly significant correlation of r2 = 0.984 with a standard deviation of only 0.49 between the calculated values of the free energies of dissociation and the experimental pKa values was found, without any special adjustment of the method. Thus, we have a theoretical a priori prediction method for pKa, which has the regression constant and the slope as only adjusted parameters. Such a method can be of great value in many areas of physical chemistry, especially in pharmaceutical and agrochemical industry. To our surprise, the slope of pKa vs ΔGdiss is only 58% of the theoretically expected value of 1/RTln(10). A careful analysis with respect to different contributions as well as a comparison with the work of other authors excludes the possibility that the discrepancy is due to weaknesses of the calculation method. Hence, we must conclude that the experimental pKa scale depends differently on the free energy of dissociation than generally assumed