Hydrophobic Molecular Similarity from MST Fractional Contributions to the Octanol/water Partition Coefficient

Summary The use of a recently proposed hydrophobic similarity index for the alignment of molecules and the prediction of their differences in biological activity is described. The hydrophobic similarity index exploits atomic contributions to the octanol/water transfer free energy, which are evaluated by means of the fractional partitioning scheme developed within the framework of the Miertus-Scrocco-Tomasi continuum model. Those contributions are used to define global and local measures of hydrophobic similarity. The suitability of this computational strategy is examined for two series of compounds (ACAT inhibitors and 5-HT₃ receptor agonists), which are aligned to maximize the global hydrophobic similarity using a Monte Carlo-simulated protocol. Indeed, the concept of local hydrophobic similarity is used to explore structure–activity relationships in a series of COX-2 inhibitors. Inspection of the 3D distribution of hydrophobic/hydrophilic contributions in the aligned molecules is valuable to identify regions of very similar hydrophobicity, which can define pharmacophoric recognition patterns. Moreover, low similar regions permit to identify structural elements that modulate the differences in activity between molecules. Finally, the quantitative relationships found between the pharmacological activity and the hydrophobic similarity index points out that not only the global hydrophobicity, but its 3D distribution, is important to gain insight into the activity of molecules. J.M.M. and S.P. have contributed equally to this study.     

Quantum chemical model of solvation for calculation of electrode potentials of redox processes involving ferrocene,cobaltocene, and their ions

Quantum chemical calculations of solvation energy for ferrocene and cobaltocene molecules and their ionic forms in water, acetonitrile, methanol, and acetone are performed in terms of the B3LYP density functional method by taking into account solvation effects and using the polarized continuum model (PCM). Standard electrode potentials of the corresponding redox pairs, the effect of solvent on them, and the overall energy of the transfer of cobaltocene cation and anion between two solvents are calculated. The calculation results well agree with the available experimental data. The present study provides sufficiently reliable grounds for the application of an ion—metallocene molecule redox pair as a pilot system for the comparison of electrode potentials and solvation energies in different solvents.     

1H NMR spectra of ethane‐1,2‐diol and other vicinal diols in benzene: GIAO/DFT shift calculations

The proton NMR spectra of several 1,2‐diols in benzene have been analysed so as to associate each magnetically nonequivalent proton with its chemical shift. The shifts and coupling constants of the OH and methylene protons of ethane‐1,2‐diol have been determined in a wide range of solvents. The conformer distribution and the proton NMR shifts of these 1,2‐diols in benzene have been computed on the basis of density functional theory. The solvent is included using the integral–equation–formalism polarizable continuum model implemented in Gaussian 09. Relative Gibbs energies for all stable conformers are calculated at the Perdew, Burke and Enzerhof (PBE)0/6‐311 + G(d,p) level, and shifts are calculated using the gauge‐including atomic orbital method with the PBE0/6‐311 + G(d,p) geometry but using the cc‐pVTZ basis set. Previous calculations on ethane‐1,2‐diol and propane‐1,2‐diol have been corrected and extended. New calculations on tert‐butylethane‐1,2‐diol, phenylethane‐1,2‐diol, butane‐2,3‐diols (dl and meso) and cyclohexane‐1,2‐diols (cis and trans) are presented. Overall, the computed NMR shifts are in good agreement with experimental values for the OH protons but remain systematically high for CH protons. Some results based on the Gaussian 03 solvation model are included for comparison. Copyright © 2012 John Wiley & Sons, Ltd.     

Activation entropy of electron transfer reactions

We report microscopic calculations of free energies and entropies for intramolecular electron transfer reactions. The calculation algorithm combines the atomistic geometry and charge distribution of a molecular solute obtained from quantum calculations with the microscopic polarization response of a polar solvent expressed in terms of its polarization structure factors. The procedure is tested on a donor–acceptor complex in which ruthenium donor and cobalt acceptor sites are linked by a four-proline polypeptide. The reorganization energies and reaction energy gaps are calculated as a function of temperature by using structure factors obtained from our analytical procedure and from computer simulations. Good agreement between two procedures and with direct computer simulations of the reorganization energy is achieved. The microscopic algorithm is compared to the dielectric continuum calculations. We found that the strong dependence of the reorganization energy on the solvent refractive index predicted by continuum models is not supported by the microscopic theory. Also, the reorganization and overall solvation entropies are substantially larger in the microscopic theory compared to continuum models.     

Study of gas-liquid partitioning of alkane solutes in several organic solvents by using principal component analysis and linear solvation energy relationships

Principal component analysis (PCA) was used to extract the number of factors which can describe the 737 gas-liquid partition coefficients of five linear, four branched, and two cyclic alkanes in 67 common solvents. Based on the reconstruction of partition coefficient data matrix, we concluded that the experimental dataset could readily be reduced to two relevant factors. Using only these two factors, there were no errors larger than 3%, 7 cases had errors larger than 2%, and in 34 cases, errors were between 1 and 2%. n-Hexane and ethylcyclohexane were chosen as the test factors, and all other partition coefficients were expressed in terms of these two test factors. Prediction of the logarithmic partition coefficient of these alkanes in seven chemically different solvents, which were originally excluded from the data matrix, was excellent: the root mean square error was 0.064, only in 11 cases the errors were larger than 1%, and only 3 had errors larger than 4%.Linear solvation energy relationships (LSERs) using both theoretical and empirical solvent parameters were used to explain the molecular interactions responsible for partition. Several combinations of parameters were tried but the standard deviations were not less than 0.31. This could be attributed to the model itself, imprecisions in the data matrix or in some of the LSER parameters. Solvent cohesive parameters and surface tension in combination with polarity-polarizability or dispersion parameters perform the best.Finally, the two principal component factors were rotated onto the most relevant physicochemical parameters that control the gas-liquid partitioning phenomena.     

Common system setup for the entire catalytic cycle of cytochrome P450(cam) in quantum mechanical/molecular mechanical studies

We describe a system setup that is applicable to all species in the catalytic cycle of cytochrome P450(cam). The chosen procedure starts from the X-ray coordinates of the ferrous dioxygen complex and follows a protocol that includes the careful assignment of protonation states, comparison between different conceivable hydration schemes, and system preparation through a series of classical minimizations and molecular dynamics (MD) simulations. The resulting setup was validated by quantum mechanical/molecular mechanical (QM/MM) calculations on the resting state, the pentacoordinated ferric and ferrous complexes, Compound I, the transition state and hydroxo intermediate of the C--H hydroxylation reaction, and the product complex. The present QM/MM results are generally consistent with those obtained previously with individual setups. Concerning hydration, we find that saturating the protein interior with water is detrimental and leads to higher structural flexibility and catalytically inefficient active-site geometries. The MD simulations favor a low water density around Asp251 that facilitates side chain rotation of protonated Asp251 during the conversion of Compound 0 to Compound I. The QM/MM results for the two preferred hydration schemes (labeled SE-1 and SE-4) are similar, indicating that slight differences in the solvation close to the active site are not critical as long as camphor and the crystallographic water molecules preserve their positions in the experimental X-ray structures.