Publications

Abstract Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) constitute a promising therapeutic option for AIDS. However, the emergence of virus-NNRTIs resistance was found to be a major problem in the field. Toward that goal, a "knock-out" strategy stands out between the several options to circumvent the problem. However the high drug or drug-drug concentrations often used generate additional safety concerns. The need for approaches able to early integrate drug- or lead-likeness, toxicity and bioavailability criteria in the drug discovery phase is an emergent issue. Given that, we propose a combined strategy based on desirability-based multiobjective optimization (MOOP) and ranking for the prioritization of HIV-1 NNRTIs hits with appropriate trade-offs between inhibitory efficacy over the HIV-1 RI and toxic effects over MT4 blood cells. Through the MOOP process, the theoretical levels of the predictive variables required to reach a desirable RI inhibitor candidate with the best possible compromise between efficacy and safety were found. This information is used as a pattern to rank the library of compounds according to a similarity-based structural criterion, providing a ranking quality of 64%/71 %/73% in training/validation/test set. A comparative study between the sequential, parallel and multiobjective virtual screening revealed that the multiobjective approach can outperform the other approaches. These results suggest that the identification of NNRTIs hits with appropriate trade-offs between potency and safety, rather than fully optimized hits solely based on potency, can facilitate the hit to lead transition and increase the likelihood of the candidate to evolve into a successful antiretroviral drug.

Abstract In the previous work, we reported a multitarget Quantitative Structure-Activity Relationship (mt-QSAR) model to predict drug activity against different fungal species. This mt-QSAR allowed us to construct a drug-drug multispecies Complex Network (msCN) to investigate drug-drug similarity (Gonzalez-Diaz and Prado-Prado, J Comput Chem 2008, 29, 656). However, important methodological points remained unclear, such as follows: (1) the accuracy of the methods when applied to other problems; (2) the effect of the distance type used to construct the msCN; (3) how to perform the inverse procedure to study species-species similarity with multidrug resistance CNs (mdrCN); and (4) the implications and necessary steps to perform a substructural Triadic Census Analysis (TCA) of the msCN. To continue the present series with other important problem, we developed here a mt-QSAR model for more than 700 drugs tested in the literature against different parasites (predicting antiparasitic drugs). The data were processed by Linear Discriminate Analysis (LDA) and the model classifies correctly 93.62% (1160 out of 1239 cases) in training. The model validation was carried out by means of external predicting series, the model classified 573 out of 607, that is, 94.4% of cases. Next, we carried out the first comparative study of the topology of six different drug-drug msCNs based on six different distances such as Euclidean, Chebychev, Manhattan, etc. Furthermore, we compared the selected drug-drug msCN and species-species mdsCN with random networks. We also introduced here the inverse methodology to construct species-species msCN based on a mt-QSAR model. Last, we reported the first substructural analysis of drug-drug msCN using Triadic Census Analysis (TCA) algorithm. (c) 2009 Wiley Periodicals, Inc. J Comput Chem 31: 164-173, 2010

Abstract Differential capacity-potential curves, C(E), were obtained from electrochemical impedance spectra (12 kHz-2 Hz) for the interfaces between Hg and a series of alkyl imidazolium-based room temperature ionic liquids having the same anion, bis(trifluoromethanesulfonyl) imide: 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl) imide [EMIM][Tf(2)N], 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl) imide [BMIM][Tf(2)N], 1-hexyl-3-methylimidazolium bis(trifluoromethanesulfonyl) imide [HMIM][Tf(2)N]. The electrocapillary curves were obtained from drop time measurements and the values of the pzc were calculated. The pzc apparently becomes more negative as the imidazolium alkyl chain length increases. A small effect of the cation is seen on the C(E) curves at negative potentials. The effect of the aromatic nature of the cation is assessed by comparing 1-butyl-1-methylimidazolium bis(trifluoromethanesulfonyl) imide, with 1-butyl-3-methylpyrrolidinium bis(trifluoromethanesulfonyl) imide [BMPyr][Tf(2)N]. The effects of temperature on the capacitance, drop time electrocapillary curve and on the pzc were also obtained. The capacity was found to increase with increasing temperature in the whole range of accessible potentials.

Abstract Mixtures of ionic surfactants of opposite charge ("catanionic" mixtures) show strongly nonideal behaviors, for example, in terms of evolution of surface tension, critical micelle concentration, or morphology with respect to composition in each surfactant. In several catanionic systems, it has been proposed that the interaction between both surfactants is so strong that lateral phase segregation occurs within bilayers, with crystallites of preferential composition demixing from the excess of the other surfactant. Here, we investigate the temperature-composition phase diagram of the myristic acid/cetyltrimethylammonium mixtures. Combining microcalorimetry, X-ray diffusion, and solid-state deuterium NMR, we demonstrate that no separation is observed in the gel (L(beta)) state. The catanionic mixtures therefore behave like two-dimensional solid solutions with a negative azeotrope: the existence of a composition at which a maximum in melting temperature is observed does not imply the existence of a preferential crystal of this composition, but results from the preferential attraction between unlike amphiphilic molecules. Additionally, this study reveals the presence of a so-called intermediate phase, that is, a phase that shows dynamic properties intermediate between that of the L(beta) and the L(alpha) phases.

Abstract Cocaine and heroin are frequently co-abused by humans, in a combination known as speedball. Recently. chemical interactions between heroin (Her) or its metabolite morphine (Mor) and cocaine (Coc) were described, resulting in the formation of strong adducts. In this work, we evaluated whether combinations of Coc and Her affect the neurotoxicity of these drugs, using rat cortical neurons incubated with Coc, Her, Her followed by Coc (Her + Coc) and Her plus Coc (Her:Coc, 1:1). Neurons exposed to Her, Her + Coc and Her:Coc exhibited a decrease in cell viability, which was more pronounced in neurons exposed to Her and Her + Coc, in comparison with neurons exposed to the mixture (Her:Coc). Cells exposed to the mixture showed increased intracellular calcium and mitochondrial dysfunction, as determined by a decrease in intracellular ATP levels and in mitochondrial membrane potential, displaying both apoptotic and necrotic characteristics. Conversely, a major increase in cytochrome c release, caspase 3-dependent apoptosis, and decreased metabolic neuronal viability were observed upon sequential exposure to Her and Coc. The data show that drug combinations potentiate cortical neurotoxicity and that the mode of co-exposure changes cellular death pathways activated by the drugs, strongly suggesting that chemical interactions occurring in Her:Coc, such as adduct formation, shift cell death mechanisms towards necrosis. Since impairment of the prefrontal cortex is involved in the loss of impulse control observed in drug addicts, the data presented here may contribute to explain the increase in treatment failure observed in speedball abusers.

Abstract Although a great variety of classical force fields (FFs) for room-temperature ionic liquids (RTTLs) have been recently suggested, no systematically derived non-polarizable model is able to reproduce their transport properties, i.e. diffusion constants, conductivities and viscosities. In the present paper, we show that modern FFs greatly overestimate pairwise electrostatic interaction energies in the RTILs systems leading to extremely hindered ionic motions. Based on the results of our ab initio molecular dynamics calculations using explicit ionic environment, we modified the electrostatic interaction potential of 1-ethyl-3-methylimidazolium tetrafluoroborate. Starting from FF, originally derived by Liu et al., we further refined it, so that it reproduces experimental transport properties without compromizing either structure or thermodynamics. The main advantages of the suggested phenomenological account for electronic polarization are its consistency, clearness, simplicity and the possibility to improve functionality of the existing FFs by modifying exclusively atomic partial electrostatic charges. ©The Electrochemical Society.

Abstract The action of sinapic acid and its alkyl esters as potential antioxidants has been investigated. For this purpose, a series of sinapic acid ester derivatives was synthesized and their antioxidant activities were evaluated using distinctive analytical methods, namely, 2,2-diphenyl-1-picrylhydrazyl (DPPH) and FRAP UV-vis methods and differential scanning calorimetry. The electron-donating activity and lipophilicity of these phenolic compounds were also evaluated. From the overall results it was concluded that alkyl ester sinapates (linear alkyl esters) present almost the same antioxidant activity, albeit slightly lower, exhibited by the parent compound (sinapic acid). Furthermore, the addition of an alkyl ester side chain has a positive effect on the partition coefficient of sinapic acid, improving its utility as an antioxidant in a more lipophilic medium. The data on the antioxidant activity obtained by different analytical methods correlated well with each other and have revealed interesting antioxidant data of alkyl esters of sinapic acid.

Abstract Chromone carboxylic acids were evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. The biological data indicated that only chromone-3-carboxylic acid is a potent hMAO-B inhibitor, with a high degree of selectivity for hMAO-B compared to hMAO-A. Conversely the chromone-2-carboxylic acid resulted almost inactive against both MAO isoforms. Docking experiments were performed to elucidate the reasons of the different MAO IC(50) data and to explain the absence of activity versus selectivity, respectively.