André Melo

Computational ecotoxicology: simultaneous prediction of ecotoxic effects of nanoparticles under different experimental conditions.

Nanotechnology has brought great advances to many fields of modern science. A manifold of applications of nanoparticles have been found due to their interesting optical, electrical, and biological/chemical properties. However, the potential toxic effects of nanoparticles to different ecosystems are of special concern nowadays. Despite the efforts of the scientific community, the mechanisms of toxicity of nanoparticles are still poorly understood. Quantitative-structure activity/toxicity relationships (QSAR/QSTR) models have just started being useful computational tools for the assessment of toxic effects of nanomaterials. But most QSAR/QSTR models have been applied so far to predict ecotoxicity against only one organism/bio-indicator such as Daphnia magna. This prevents having a deeper knowledge about the real ecotoxic effects of nanoparticles, and consequently, there is no possibility to establish an efficient risk assessment of nanomaterials in the environment. In this work, a perturbation model for nano-QSAR problems is introduced with the aim of simultaneously predicting the ecotoxicity of different nanoparticles against several assay organisms (bio-indicators), by considering also multiple measures of ecotoxicity, as well as the chemical compositions, sizes, conditions under which the sizes were measured, shapes, and the time during which the diverse assay organisms were exposed to nanoparticles. The QSAR-perturbation model was derived from a database containing 5520 cases (nanoparticle-nanoparticle pairs), and it was shown to exhibit accuracies of ca. 99% in both training and prediction sets. In order to demonstrate the practical applicability of our model, three different nickel-based nanoparticles (Ni) with experimental values reported in the literature were predicted. The predictions were found to be in very good agreement with the experimental evidences, confirming that Ni-nanoparticles are not ecotoxic when compared with other nanoparticles. The results of this study thus provide a single valuable tool toward an efficient prediction of the ecotoxicity of nanoparticles under multiple experimental conditions.

Calibration sets and the accuracy of vibrational scaling factors: A case study with the X3LYP hybrid functional

A linear least-squares methodology was used to determine the vibrational scaling factors for the X3LYP density functional. Uncertainties for these scaling factors were calculated according to the method devised by Irikura et al. [J. Phys. Chem. A 109, 8430 (2005)]. The calibration set was systematically partitioned according to several of its descriptors and the scaling factors for X3LYP were recalculated for each subset. The results show that the scaling factors are only significant up to the second digit, irrespective of the calibration set used. Furthermore, multivariate statistical analysis allowed us to conclude that the scaling factors and the associated uncertainties are independent of the size of the calibration set and strongly suggest the practical impossibility of obtaining vibrational scaling factors with more than two significant digits.

Towards the Discovery of a Novel Class of Monoamine Oxidase Inhibitors: Structure–Property–Activity and Docking Studies on Chromone Amides

Monoamine oxidase (MAO) is a mammalian enzyme present in two isoforms (MAO-A and MAO-B) that is localized on the outer mitochondrial membrane and is involved in the oxidative deamination of exogenous and endogenous amines. Due to their central role in neurotransmitter metabolism, these isoforms represent attractive drug targets. In fact, MAO-A inhibitors are frequently used as antidepressants and antianxiety agents, while MAO-B inhibitors are relevant tools in the therapy of Alzheimer’s and Parkinson’s diseases. The chromone scaffold (4H)-1-benzopyran-4-one has been recognized as a putative pharmacophore for several targets. It has been recently studied as a valid scaffold for the design of selective MAO-B inhibitors. Furthermore, the simplicity of its synthesis make chromone carboxamide derivatives attractive to medicinal chemists. Recent data obtained by our group has shown that the presence of the same type of substituents on the 2or 3-position of the pyrone ring discloses different pharmacological profiles—a circumstance that can be illustrated with the following chromone isomers: N-phenyl-4oxo-4H-chromone-2-carboxamide (1) and N-phenyl-4-oxo-4Hchromone-3-carboxamide (2) ; the former is inactive, while the latter is a selective and potent MAO-B inhibitor : IC50 (hMAOB) = 0.40 0.022 mm, selectivity index (SI) >250. To gain insight into the physicochemical properties that determine the activity of these types of benzopyran derivatives (1 and 2), it was decided to further explore the regiospecificity of the carboxamide function by acquiring relevant theoretical and spectroscopic data. From the conformational analysis of chromones 1 and 2, it can be concluded that the diagram of the relative potential energy of the two isomers shows that they have different profiles (Figure 1). The energetic difference between the minima detected suggests the presence of an added stabilizing driving force, for example, an intramolecular hydrogen bond in chromone 2 (Figure 2). Conformational analysis also shows that, because of the presumed hydrogen bond, the structure of chromone 2 is much more rigid than that of 1 (Figure 2). Therefore, a subsequent study evaluating the thermodynamic stability of the most relevant prototropic tautomers/rotomers of compound 2 in the gas phase, while taking solvent effects into account, was performed. Accordingly, the presumed existence of the two species stabilized by intramolecular hydrogen bonds (amide 2 a/iminol 2 c tautomers) was included. The data clearly indicates that, in the gas phase, tautomers 2 b and 2 c are thermodynamically unstable when compared to tautomer 2 a. The significance of the hydrogen bond as a stabilizing force on the structure of 2 can be explained by the relatively large enthalpies (see Table 1). Since preliminary calculations showed that the iminol tautomer (2 c) was approximately 15 kcal mol 1 higher in energy, it was deemed energetically unfavorable and consequently omitted from subsequent studies. In order to provide experimental evidence for the presence of the hydrogen bond, NMR spectra (acquired in CDCl3 and DMSO) were collected and analyzed. The data obtained so far corroborates the presence, in solution, of a strong intramolecular hydrogen bond in compound 2 (Table 2). 6] The strong hy[a] A. Gaspar, Prof. N. Milhazes, Prof. F. Borges CIQUP, Departamento de Qu mica e Bioqu mica Faculdade de CiÞncias, Universidade do Porto Rua Campo Alegre 687, 4169-007 Porto (Portugal) Fax: (+ 351) 220 402 009 E-mail : fborges@fc.up.pt [b] Dr. F. Ortuso, Prof. S. Alcaro Dipartimento di Scienze Farmacobiologiche Universit “Magna Græcia” di Catanzaro Complesso “Nin Barbieri”, 88021, Roccelletta di Borgia, Catanzaro (Italy) Fax: (+ 39) 0961391490 E-mail : alcaro@unicz.it [c] F. Teixeira, Prof. A. Melo, Prof. M. N. D. S. Cordeiro REQUIMTE, Departamento de Qu mica e Bioqu mica Faculdade de CiÞncias, Universidade do Porto, Porto (Portugal) [d] Prof. E. Uriarte Departamento de Quimica Organica, Faculdad de Farmacia Universidad de Santiago de Compostela Avda. das Ciencias, 15782 Santiago de Compostela (Spain) [e] Prof. N. Milhazes Instituto Superior de CiÞncias de Safflde-Norte R. Central de Gandra, 1317 Gandra PRD (Portugal) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.201000452. 1 Note : the polar aprotic solvent characteristics of DMSO are excellent for hydrogen bond acceptance that to some extent can disrupt the hydrogen bond that is being sought out via NMR by forming intermolecular hydrogen bonds between itself and the system under study.

Theoretical study of arginine-carboxylate interactions

The importance of the guanidinium‐carboxylate interactions has sprung from the observed salt bridges often present in biological systems involving the arginine‐glutamate or arginine‐aspartate side chains. The strength of these interactions has been explained on the basis of a great coulombic energy gain, due to the closeness of two charges of opposite sign and the occurrence of H-bond interactions. However, in some environments proton transfer, from guanidinium to carboxylate, can occur with the consequent annihilation of charge. In this work, both ab-initio (6-31G** and MP2/6-31G**) and semi-empirical (AM1) calculations were performed in vacuo on appropriate models, methylguanidinium ‐acetate and methylguanidine‐acetic acid to simulate the zwitterionic and the neutral forms, respectively. The results obtained indicate that, in solvent-free hydrophobic environments, the neutral form should be more stable than the zwitterionic one. q 1999 Elsevier Science B.V. All rights reserved.

Structural and thermodynamic characterization of polyphenylbenzenes

The thermodynamic and structural study of a series of polyphenylbenzenes, from benzene, n(Ph) = 0, to hexaphenylbenzene, n(Ph) = 6, is presented. The available literature data for this group of compounds was extended by the determination of the relevant thermodynamic properties for 1,2,4-triphenylbenzene, 1,2,4,5-tetraphenylbenzene, and hexaphenylbenzene, as well as structural determination by X-ray crystallography for some of the studied compounds. Gas phase energetics in this class of compounds was analyzed from the derived standard molar enthalpies of formation in the gaseous phase. The torsional profiles relative to the phenyl-phenyl hindered rotations in some selected polyphenylbenzenes, as well as the gas phase structures and energetics, were derived from quantum chemical calculations. In the ideal gas phase, a significant enthalpic destabilization was observed in hexaphenylbenzene relative to the other polyphenylbenzenes, due to steric crowding between the six phenyl substituents. A relatively low enthalpy of sublimation was observed for hexaphenylbenzene, in agreement with the decreased surface area able to establish intermolecular interactions. The apparently anomalous low entropy of sublimation observed for hexaphenylbenzene is explained by its high molecular symmetry and the six highly hindered phenyl internal rotations. For the series of polyphenylbenzenes considered, it was shown that the differentiation in the entropy of sublimation can be chiefly ascribed to the torsional freedom of the phenyl substituents in the gas phase and the entropy terms related with molecular symmetry.

Solvent Accessible Surface Area-Based Hot-Spot Detection Methods for Protein−Protein and Protein−Nucleic Acid Interfaces

Due to the importance of hot-spots (HS) detection and the efficiency of computational methodologies, several HS detecting approaches have been developed. The current paper presents new models to predict HS for protein-protein and protein-nucleic acid interactions with better statistics compared with the ones currently reported in literature. These models are based on solvent accessible surface area (SASA) and genetic conservation features subjected to simple Bayes networks (protein-protein systems) and a more complex multi-objective genetic algorithm-support vector machine algorithms (protein-nucleic acid systems). The best models for these interactions have been implemented in two free Web tools.

Controversies in Posttraumatic Epilepsy

In civilian accidents the factors involved in the origin of posttraumatic epilepsy are controversial. In this study of 506 consecutive head trauma patients and 101 epileptic patients developing seizures after head trauma, we have examined the importance of the duration of coma, type of seizure and drug therapy, time to first seizure, age and focal lesions and compared our results with the literature. The importance is stressed of focal lesions and of neurological deficits for the origin of posttraumatic seizures.

Affinity prediction on A3 adenosine receptor antagonists: The chemometric approach

Potent and selective ligands with a nucleoside skeleton are generally thought as agonists of the human A(3) adenosine receptor (AR), however, some of them can also act as full antagonists. This work reports a Quantitative Structure-Activity Relationship (QSAR) study for predicting the binding affinity of such type of compounds towards the A(3) AR. Several different theoretical molecular descriptors, calculated only on the basis of knowledge of the molecular structure and an efficient variable selection procedure, such as forward stepwise regression, led to models with satisfactory accuracy and predictive ability. But the best-final QSAR model is based on the Molecule Representation of Structures based on Electron diffraction (3D-MoRSE) descriptors capturing a reasonable interpretation. This QSAR model is able to explain more than 85% of the variance in the experimental affinity and manifests good predictive ability as indicated by the higher Q(2)s of cross- and external-validations. The model obtained in this study may provide guidance for future design of new potent and selective human A(3) AR full antagonists with a nucleoside skeleton.

Proton transfer in arginine-carboxylate interactions

Abstract Arginine-carboxylate interactions in proteins have aroused much interest due to the important role they play in the stability of biological systems. These interactions have usually been interpreted as being associated with a zwitterionic state as opposed to a neutral one. In this work, ab initio (6–31G ∗∗ basis set) calculations were carried out in vacuo on appropriate models, methylguanidinium-acetate and methylguanidine-acetic acid, to simulate the zwitterionic and neutral forms, respectively. The results obtained reveal that the neutral form is more stable than the zwitterion, i.e. proton transfer should occur with the consequent annihilation of charge in some environments, possibly hydrophobic ones.

Unusual color change of vinylpyranoanthocyanin-phenolic pigments.

Anthocyanins are responsible for an interesting variety of colors in flowers, red fruits, and plant-derived foodstuffs. Experimental evidence is presented supporting an unusual color change from red to blue during storage. It has been investigated as a function of temperature at constant pH (pH <2). The color properties of the vinylpyranoanthocyanin pigments, usually designated portisins, have been studied in this work using both experimental and theoretical techniques. The visible spectra obtained from the two approaches were in good agreement. This behavior was explained by a reversible physical-chemical change due to electronic and vibrational properties.