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Within the scope of SAMPL7 challenge for predicting physical properties, the Integral Equation Formalism of the Miertus-Scrocco-Tomasi (IEFPCM/MST) continuum solvation model has been used for the blind prediction of n-octanol/water partition coefficients and acidity constants of a set of 22 and 20 sulfonamide-containing compounds, respectively. The log P and pKa were computed using the B3LPYP/6-31G(d) parametrized version of the IEFPCM/MST model. The performance of our method for partition coefficients yielded a root-mean square error of 1.03 (log P units), placing this method among the most accurate theoretical approaches in the comparison with both globally (rank 8th) and physical (rank 2nd) methods. On the other hand, the deviation between predicted and experimental pKa values was 1.32 log units, obtaining the second best-ranked submission. Though this highlights the reliability of the IEFPCM/MST model for predicting the partitioning and the acid dissociation constant of drug-like compounds compound, the results are discussed to identify potential weaknesses and improve the performance of the method. [ABSTRACT FROM AUTHOR]

The IEFPCM/MST continuum solvation model is used for the blind prediction of n-octanol/water partition of a set of 11 fragment-like small molecules within the SAMPL6 Part II Partition Coefficient Challenge. The partition coefficient of the neutral species (log P) was determined using an extended parametrization of the B3LYP/6-31G(d) version of the Miertus–Scrocco–Tomasi continuum solvation model in n-octanol. Comparison with the experimental data provided for partition coefficients yielded a root-mean square error (rmse) of 0.78 (log P units), which agrees with the accuracy reported for our method (rmse = 0.80) for nitrogen-containing heterocyclic compounds. Out of the 91 sets of log P values submitted by the participants, our submission is within those with an rmse < 1 and among the four best ranked physical methods. The largest errors involve three compounds: two with the largest positive deviations (SM13 and SM08), and one with the largest negative deviations (SM15). Here we report the potentiometric determination of the log P for SM13, leading to a value of 3.62 ± 0.02, which is in better agreement with most empirical predictions than the experimental value reported in SAMPL6. In addition, further inclusion of several conformations for SM08 significantly improved our results. Inclusion of these refinements led to an overall error of 0.51 (log P units), which supports the reliability of the IEFPCM/MST model for predicting the partitioning of neutral compounds. [ABSTRACT FROM AUTHOR]

A first-order perturbation treatment of the polarization contribution to the free energy of hydration is presented. Very simple expressions for the computation of the total electrostatic free energy of solvation, the polarization contribution, and its components (distortion and stabilization) are derived. These equations can be used with either continuum (quantum and classical) or discrete approaches. The reliability of these equations is examined by comparison with rigorous expressions derived previously within the framework of the self-consistent reaction field theory. Indeed, the suitability of the classical expressions for the distortion and stabilization terms used in the context of discrete strategies has been explored by comparison between self-consistent reaction field and molecular dynamics–free-energy perturbation results. The excellent agreement found between the two techniques allows us to envisage a procedure to account for the polarization in force field-derived methods. © 1995 American Institute of Physics. [ABSTRACT FROM AUTHOR]

The effect of solvation, as studied by the self-consistent reaction field procedure, on the shapes, sizes, and anisotropies of eight small prototypical anions (OH-, NH-2, CH-3, CN-, SH-, N-3, NO-2, and NO-3) has been studied at the ab initio 6–31++G(d) level. Both the general molecular electrostatic potential distribution and the molecular electrostatic potential topography have been used for examining the effect of solvation. The results demonstrate both the complexity and specificity of the hydration effect on the solute charge distribution. It is observed that in general anions tend to shrink upon solvation. The molecular electrostatic potential, in general, becomes more negative and the electron density is increased upon solvation. The effect of the solvation on the chemical reactivity and anisotropy of the anions in aqueous environment is discussed. [ABSTRACT FROM AUTHOR]

Since the development of structure-activity relationships about 50 years ago, 3D-QSAR methods belong to the most refined ligand-based in silico techniques for prediction of biological data using physicochemical molecular fields. In this scenario, this study reports the development and validation of quantum mechanical (QM)-based hydrophobic descriptors derived from the parametrized MST continuum solvation model to be used in 3D-QSAR studies within the framework of the Hydrophobic Pharmacophore (HyPhar) method. To this end, five sets of compounds reported in the literature (dopamine D2/D4 antagonists, antifungal 2-aryl-4-chromanones, and inhibitors of GSK-3, cruzain and thermolysin) have been revisited. The results derived from the QM/MST-based hydrophobic descriptors have been compared with previous CoMFA and CoMSIA studies, and examined in light of the available X-ray crystallographic structures of the targets. The analysis reveals that the combination of electrostatic and nonelectrostatic components of the octanol/water partition coefficient yields pharmacophoric models fully comparable with the predictive potential of standard 3D-QSAR techniques. Moreover, the graphical representation of the hydrophobic maps provides a direct linkage with the pattern of interactions found in crystallographic structures. Overall, the introduction of the QM/MST-based descriptors, which could be easily adapted to other continuum solvation formalisms, paves the way to novel computational strategies for disclosing structure-activity relationships in drug design. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

This study reports the application of the quantum mechanical self-consistent reaction field MST method to compute the solvation profile in water of the twenty natural amino acids. The aim is to derive intrinsic fractional contributions to the hydration free energy and to examine their transferability to peptides. To this end, IEF-MST calculations have been performed at the B3LYP/6-31G(d) level for the series of acetyl amino acid amides, which were chosen as model compounds. In order to account for the flexibility of both the backbone and the side chain in deriving the hydration fractional contributions, calculations have been performed for representative conformers taken from the Dunbrack's backbone-dependent conformational library. The results allow us to dissect the hydration free energy into backbone and side chain contributions and examine the conformational dependence of the fragmental contributions to hydration. For the backbone, different hydration contributions are found for α-helical and β-sheet conformations, which mainly reflect differences in the electrostatic contribution to hydration of the carbonyl group. In contrast, the conformational flexibility of the side chain is found to have little impact on the fractional contribution to hydration. These findings should be valuable to refine semiempirical methods for predicting solvation properties of peptides and proteins in large-scale genomic studies. [ABSTRACT FROM AUTHOR]

The IEF-MST continuum solvation model is used to predict the hydration free energies and tautomeric preferences of a set of multifunctional compounds compiled as a blind test for computational solvation methods in the SAMPL2 contest. Computations of hydration free energies was performed using both HF/6-31G(d) and B3LYP/6-31G(d) versions of the IEF-MST model. For tautomeric preferences, the IEF-MST data was combined with the gas phase free energy differences predicted at different levels of theory ranging from MP2/6-31+G(d) to MP2/CBS+[CCSD-MP2/6-31+G(d)] levels. Comparison with the experimental data provided for hydration free energies yields a root-mean square deviation (rmsd) close to 2.3 kcal/mol, which is quite remarkable, especially considering the reduced set of training compounds used in the parametrization of the IEF-MST method. With regard to tautomerism, the lowest error in the prediction of the relative stabilities between tautomers in solution is obtained by combining MP2/CBS+[CCSD-MP2/6-31+G(d)] results with IEF-MST hydration free energies, yielding a rmsd of ca. 3.4 kcal/mol. The results illustrate the delicate balance that must be kept between the intrinsic relative stabilities in the gas phase and the differential hydration preferences in order to obtain an accurate description of the prototropic tautomerism in bioorganic compounds. [ABSTRACT FROM AUTHOR]

The need to simulate large-sized molecules or to deal with large series of compounds is a challenging topic in computational chemistry, which has stimulated the development of accurate semiempirical methods, such as the recently reported Recife Model 1 (RM1; J Comput Chem 2006, 27, 1101). Even though RM1 may prove to be of value simply due to the enhanced quantitative accuracy in gas phase, it is unclear how the new parameters optimized for RM1 affect the suitability of this semiempirical Hamiltonian to study chemical processes in condensed phases. To address this question, we report the parametrization of the MST/RM1 continuum model for neutral solutes in water, octanol, chloroform and carbon tetrachloride, and for ions in water. The results are used to discuss the transferability of the solvation parameters implemented in previous MST/AM1 and MST/PM3 models. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008 [ABSTRACT FROM AUTHOR]

We report a systematic comparison of the dispersion and repulsion contributions to the free energy of solvation determined using quantum mechanical self-consistent reaction field (QM-SCRF) and classical methods. In particular, QM-SCRF computations have been performed using the dispersion and repulsion expressions developed in the framework of the integral equation formalism of the polarizable continuum model, whereas classical methods involve both empirical pairwise potential and surface-dependent approaches. Calculations have been performed for a series of aliphatic and aromatic compounds containing prototypical functional groups in four solvents: water, octanol, chloroform, and carbon tetrachloride. The analysis is focused on the dependence of the dispersion and repulsion components on the level of theory used in QM-SCRF computations, the contribution of those terms in different solvents, and the magnitude of the coupling between electrostatic and dispersion–repulsion components. Finally, comparison is made between the dispersion–repulsion contributions obtained from QM-SCRF calculations and the results determined from classical approaches. © 2006 Wiley Periodicals, Inc. J Comput Chem, 2006 [ABSTRACT FROM AUTHOR]

Provides information on the approaches used for the description of solvation in systems of biological importance. Definition of a solvent; Nature of the solvent effect; Information on the Monte Carlo and molecular dynamics modeling of the solvated system nature; Discussion on quantum mechanics and molecular mechanics methods.

Hydrophobicity is a key physicochemical descriptor used to understand the biological profile of (bio)organic compounds as well as a broad variety of biochemical, pharmacological, and toxicological processes. This property is estimated from the partition coefficient between aqueous and nonaqueous environments for neutral compounds (PN) and corrected for the pH-dependence of ionizable compounds as the distribution coefficient (D). Here, we have extended the parametrization of the Miertus-Scrocco-Tomasi continuum solvation model in n-octanol to nitrogen-containing heterocyclic compounds, as they are present in many biologically relevant molecules (e.g., purines and pyrimidines bases, amino acids, and drugs), to obtain accurate log PN values for these molecules. This refinement also includes solvation calculations for ionic species in n-octanol with the aim of reproducing the experimental partition of ionic compounds (PI). Finally, the suitability of different formalisms to estimate the distribution coefficient for a wide range of pH values has been examined for a set of small acidic and basic compounds. The results indicate that in general the simple pH-dependence model of the ionizable compound in water suffices to predict the partitioning at or around physiological pH. However, at extreme pH values, where ionic species are predominant, more elaborate models provide a better prediction of the n-octanol/water distribution coefficient, especially for amino acid analogues. Finally, the results also show that these formalisms are better suited to reproduce the experimental pH-dependent distribution curves of log D for both acidic and basic compounds as well as for amino acid analogues. [ABSTRACT FROM AUTHOR]

Abstract: An extension of the Miertus–Scrocco–Tomasi (MST) continuum method to the Integral Equation Formalism (IEF) is presented. In particular, we report here the parametrization of the MST(IEF) model to the solvation in water, octanol, chloroform and carbon tetrachloride. A detailed comparison is made between the results obtained from the MST(PCM) formalism corrected by using diverse charge normalization schemes and those obtained from the IEF formalism. The IEF method is found to provide results in close agreement with those obtained within the PCM framework by taking into account the anisotropy of the solute''s charge distribution in the charge normalization of the apparent surface charge that simulates the solvent reaction field. Besides the standard HF/6-31G(d) level of theory considered in previous parametrizations of the MST(PCM) model, we also report here the results obtained for the B3LYP hybrid density functional method. These results indicate that there are small differences in the electrostatic component of the solvation free energy determined from HF and B3LYP levels of theory, which might be captured by suitable adjustment of the atomic surface tensions in the van der Waals component. Overall, the results support the strategy used in the development of the MST model and its suitability as a robust approach to the study of molecules in solution. [Copyright &y& Elsevier]