Mathematical models under conditions of cyclic staircase voltammetry and electrochemical impedance spectroscopy (EIS), which,consider the kinetic effects due to the complexation reaction by the facilitated transfer of metal ions at polarized interfaces, are presented. Criteria for qualitative recognition of these kinetic effects from the features of simulated cyclic voltammograms are given. In case of the existence of these effects, only the EIS can bring access to the thermodynamics and kinetics of the complexation chemical reaction. Analytical equations for estimating the thermodynamic parameters by such systems under EIS conditions are evaluated. The theoretical results are compared with the experimental results of the facilitated Cu2+ transfer at the polarized water(-)1,2-dichlorethane interface, assisted by two phenanthroline-containing macrocycles. In the experimental case where kinetic effects due to the complexation step exist, we show how elegantly EIS can be used as a too] for estimation of the complexation constant of Cu2+ and 5-oxo-2,8-dithia [9],(2,9)-1,10-phenanthrolinophane (PhenOS(2)).

Up to now, very few applications of multiobjective optimization (MOOP) techniques to quantitative structure-activity relationship (QSAR) studies have been reported in the literature. However, none of them report the optimization of objectives related directly to the final pharmaceutical profile of a drug. In this paper, a MOOP method based on Derringer's desirability function that allows conducting global QSAR studies, simultaneously considering the potency, bioavailability, and safety of a set of drug candidates, is introduced. The results of the desirability-based MOOP (the levels of the predictor variables concurrently producing the best possible compromise between the properties determining an optimal drug candidate) are used for the implementation of a ranking method that is also based on the application of desirability functions. This method allows ranking drug candidates with unknown pharmaceutical properties from combinatorial libraries according to the degree of similarity with the previously determined optimal candidate. Application of this method will make it possible to filter the most promising drug candidates of a library (the best-ranked candidates), which should have the best pharmaceutical profile (the best compromise between potency, safety and bioavailability). In addition, a validation method of the ranking process, as well as a quantitative measure of the quality of a ranking, the ranking quality index (W), is proposed. The usefulness of the desirability-based methods of MOOP and ranking is demonstrated by its application to a library of 95 fluoroquinolones, reporting their gram-negative antibacterial activity and mammalian cell cytotoxicity. Finally, the combined use of the desirability-based methods of MOOP and ranking proposed here seems to be a valuable tool for rational drug discovery and development.

Up to now, very few reports have been published concerning the application of multiobjective optimization (MOOP) techniques to quantitative structure-activity relationship (QSAR) studies. However, none reports the optimization of objectives related directly to the desired pharmaceutical profile of the drug. In this work, for the first time, it is proposed a MOOP method based on Derringer's desirability function that allows conducting global QSAR studies considering simultaneously the pharmacological, pharmacokinetic and toxicological profile of a set of molecule candidates. The usefulness of the method is demonstrated by applying it to the simultaneous optimization of the analgesic, anti inflammatory, and ulcerogenic properties of a library of fifteen 3-(3-methylplienyl)-2-substituted amino-3H-quinazolin-4-one compounds. The levels of the predictor variables producing concurrently the best possible compromise between these properties is found and used to design a set of new optimized drug candidates. Our results also suggest the relevant role of the bulkiness of alkyl substituents on the C-2 position of the quinazoline ring over the Ulcerogenic properties for this family of compounds. Finally, and most importantly, the desirability-based MOOP method proposed is a valuable toot and shall aid in the future rational design of novel successful drugs. (C) 2008 Wiley Periodicals, Inc.

The consecutive deposition of oxygen atoms on the Au(3 2 1) surface was studied carrying out calculations based in the spin polarized density functional theory within the GGA/PW91 exchange-correlation functional. The clean and oxygen covered Au(3 2 1) surfaces were modeled by a periodic supercell approach; the unit cell has 15 gold atoms, the outermost five define the (1 1 1) terrace and the step. The adsorption of a single oxygen atom is more favorable if it occurs at a fcc hollow site on the (1 1 1) terrace adjacent to the step while for the co-adsorption of two oxygen atoms on the Au(3 2 1) surface, hollow sites nearby the step are preferred. The introduction of an additional oxygen atom on the already optimized slabs containing two oxygen atoms yield, in some cases, structures with a single oxygen atom attached to the surface and an oxygen molecule far from the slab. In the other cases, several initial geometries converged to the same final structure and, in general, the adsorption of three oxygen atoms per unit cell was found to be thermodynamically unfavorable. The exception was a planar structure formed after reconstruction of the surface. The simultaneous adsorption of four oxygen atoms per unit cell is characterized by relatively high adsorption energies of -0.53 and -0.56 eV, corresponding to a porous structure containing sub-surface oxygen atoms forming a gold oxide layer and to a well ordered folded structure. The addition of a fifth oxygen atom to the structures already containing four oxygen atoms on the surface resulted in an endothermic processes suggesting that they will be hard to found even after exposure to high pressures of oxygen.

The CO oxidation on the Au(321) surface was investigated using spin polarized density functional theory based calculations within the GGA-PW91 exchange-correlation functional. This was done by studying separately the adsorption of isolated CO or CO2 and also the coadsorption of CO + O or CO + O-2 on the Au(321) surface. A periodic supercell approach was used to model the gold surface. The kinetic profile of the oxidation reaction was determined with the climbing image-nudged elastic band method and also with the dimer approach. It was found that CO adsorbs on the clean surface preferably at the kinks, and the same preference exists if atomic or molecular oxygen is coadsorbed on the Au(321) surface. CO2 is weakly adsorbed on Au(321) and appears at large distance from the metal surface. Importantly, the formation of carbonate species or of four atoms compounds, OCOO, adsorbed on the Au(321) surface is thermodynamically favorable from CO and O-2. The reaction of CO oxidation by atomic oxygen occurs almost without any energy cost on a reconstructed surface, whereas moderate barriers of similar to 0.6 eV were computed for the direct reaction with molecular oxygen occurring at the surface steps. These results suggest that the predissociation of the molecular oxygen on the Au(321) surface for the CO oxidation is energetically less favorable than the direct reaction with molecular oxygen. Finally, the products of the oxidation reaction are much more stable than the four atoms compound.

In this work, the partition method introduced by Carvalho and Melo was used to study the complex between Cucurbita maxima trypsin inhibitor (CMTI-I) and glycerol at the AM1 level. An effective potential, combining non-bonding and polarization plus charge transfer (PLCT) terms, was introduced to evaluate the magnitude of the interaction between each amino acid and the ligand. In this case study, the nonbonding-PLCT non-compensation characterizes the stabilization energy of the association process in study. The main residues (Gly29, Cys3 and Arg5) with net attractive effects and Arg1 (with a net repulsive effect), responsible by the stability of protein-ligand complex, are associated with large nonbonding energies non-compensated by PLCT effects. The results obtained enable us to conclude that the present decomposition scheme can be used for understanding the cohesive phenomena in proteins.

The gas-phase stabilities of linear, branched and cyclic silicates made of up to five silicon atoms were studied with density functional theory (DFT). The starting geometries for the DFT calculations at the B3LYP/6-311+G(2d,2p) level of theory were obtained from classical molecular dynamics simulations. We have observed that geometric parameters and charges are mainly affected by the degree of deprotonation. Charges on Si atoms are also influenced by their degree of substitution. The enthalpy of deprotonation of the neutral species was found to decrease with the size of the molecule, while the average deprotonation enthalpy of highly charged compounds increased with molecular size. Furthermore, the formation of rings in highly charged silicates is enthalpically preferred to chain growth. These observations result from two competing effects: the easier distribution of negative charge in silicates with low charge density and the strong intramolecular repulsions present in silicates with high charge density. As a consequence, highly charged silicates in the gas phase tend to be as small and as highly condensed as possible, which is in line with experimental observations from solution NMR.

We present results of molecular dynamics simulations of the interface between water and 2-nitrophenyl octyl ether (NPOE). This system is analyzed in detail using a procedure to calculate intrinsic profiles of several important properties (density, radial distribution functions, hydrogen bonds, molecular orientation, self-diffusion). The interface was found to be molecularly sharp but corrugated by thermal fluctuations. Using a method based on capillary wave theory, we have estimated the interfacial tension and obtained good agreement with values calculated from the virial route. The results were compared to simulations of the water/nitrobenzene interface. The presence of an alkyl chain in NPOE introduces an added degree of hydrophobicity, which causes an increase in the interfacial tension. Furthermore, interfacial NPOE molecules are less organized than nitrobenzene and show a distinct dynamic response. These results shed light on the observed differences between these two organic liquids in electrochemical studies.