Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1: Brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug

The first anti-HIV drug, zidovudine (AZT), was approved by the FDA a quarter of a century ago, in 1985. Currently, anti-HIV drug-combination therapies only target HIV-1 protease and reverse transcriptase. Unfortunately, most of these molecules present numerous shortcoming; such as viral resistances and adverse effects. In addition, these drugs are involved in later stages of infection. Thus, it is necessary to develop new drugs that are able to block the first steps of viral life cycle. Entry of HIV-1 is mediated by its two envelope glycoproteins: gp120 and gp41. Upon gp120 binding to cellular receptors, gp41 undergoes a series of conformational changes from a non-fusogenic to a fusogenic conformation. The fusogenic core of gp41 is a trimer-of-hairpins structure in which three C-terminal helices pack against a central trimeric-coiled coil formed by three N-terminal helices. The formation of this fusogenic structure brings the viral and cellular membranes close together, a necessary condition for membrane fusion to occur. As gp120 and gp41 are attractive targets, the development of entry inhibitors represents an important avenue of anti-HIV drug therapy. The present review will focus on some general considerations about HIV, the main characteristics of gp120, gp41 and their inhibitors, with special emphasis on the advances of computational approaches employed in the development of bioactive compounds against HIV-1 entry process

Molecular docking and 3D-quantitative structure activity relationship analyses of peptidyl vinyl sulfones: Plasmodium Falciparum cysteine proteases inhibitors

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three-dimensional quantitative structure- activity relationship (3D-QSAR) studies were conducted on a series (39 molecules) of peptidyl vinyl sulfone derivatives as potential Plasmodium Falciparum cysteine proteases inhibitors. Two different methods of alignment were employed: (i) a receptor-docked alignment derived from the structure-based docking algorithm GOLD and (ii) a ligand-based alignment using the structure of one of the ligands derived from a crystal structure from the PDB databank. The best predictions were obtained for the receptor-docked alignment with a CoMFA standard model (q(2) = 0.696 and r(2) = 0.980) and with CoMSIA combined electrostatic, and hydrophobic fields (q(2) = 0.711 and r(2) = 0.992). Both models were validated by a test set of nine compounds and gave satisfactory predictive r(2) pred values of 0.76 and 0.74, respectively. CoMFA and CoMSIA contour maps were used to identify critical regions where any change in the steric, electrostatic, and hydrophobic fields may affect the inhibitory activity, and to highlight the key structural features required for biological activity. Moreover, the results obtained from 3D-QSAR analyses were superimposed on the Plasmodium Falciparum cysteine proteases active site and the main interactions were studied. The present work provides extremely useful guidelines for future structural modifications of this class of compounds towards the development of superior antimalarials

The enthalpies of dissociation of the N-O bonds in two quinoxaline derivatives

The present work reports the first experimental thermochemical study of mono-N-oxides derived from quinoxaline, namely, 3-methoxycarbonyl-2-methyl-quinoxaline N-oxide and 3-ethoxycarbonyl-2-methyl-quinoxaline N-oxide. The values of the enthalpies of formation, in the condensed state, and of the enthalpies of sublimation, derived from static bomb calorimetry and Calvet microcalorimetry measurements, respectively, are combined to derive the standard molar enthalpies of formation in the gaseous phase for these two compounds. From the latter values, the first and second N-O bond dissociation enthalpies for the corresponding di-N-oxides have been obtained. The gas-phase experimental results are also compared with calculated data obtained with a density functional theory approach. Copyright (c) 2008 John Wiley & Sons, Ltd

Gas-phase molecular structure and energetics of anionic silicates

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

Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: Towards the development of potential dual action antimalarials

A series of cinnamic acid/4-aminoquinoline conjugates conceived to link, through a proper retro-enantio dipeptide, a heterocyclic core known to prevent hemozoin formation, to a trans-cinnamic acid motif capable of inhibiting enzyme catalytic Cys residues, were synthesized as potential dual-action antimalarials. The effect of amino acid configuration and the absence of the dipeptide spacer were also assessed. The replacement of the D-amino acids by their natural L counterparts led to a decrease in both anti-plasmodial and falcipain inhibitory activity, suggesting that the former are preferable. Molecules with such spacer were active against blood-stage Plasmodium falciparum, in vitro, and hemozoin formation, implying that the dipeptide has a key role in mediating these two activities. In turn, compounds without spacer were better falcipain-2 inhibitors, likely because these compounds are smaller and have their vinyl bonds in closer vicinity to the catalytic Cys, as suggested by molecular modeling calculations. These novel conjugates constitute promising leads for the development of new antiplasmodials targeted at blood-stage malaria parasites

Molecular simulation of silica/surfactant self-assembly in the synthesis of periodic mesoporous silicas

Understanding the synthesis of periodic mesoporous silica (PMS) is crucial for a more efficient use of these materials and is a necessary first step toward a rational design strategy for the templated synthesis of porous solids. In this paper, the early stages of the synthesis process of PMS materials are simulated directly by molecular dynamics, using realistic atomistic models. It is the first time that such computationally demanding calculations have been attempted. By comparing the self-assembly of cationic surfactants in the presence and absence of silicates, we are able to show that silica promotes the formation of larger aggregates than in a simple surfactant/water solution. The formation of these larger micelles is explained by a strong interaction of the silicate molecules with the surfactant head groups. This strong interaction increases the local concentration of silica at the surface of the micelles, which induces the formation of more condensed silicate species. The surfactant/silica structures observed here are potentially important intermediates in PMS synthesis

Toward an understanding of the aqueous solubility of amino acids in the presence of salts : a molecular dynamics simulation study

Ion-specific effects on the aqueous solubilities of biomolecules are relevant in many areas of biochemistry and life sciences. However, a general and well-supported molecular picture of the phenomena has not yet been established. In order to contribute to the understanding of the molecular-level interactions governing the behavior of biocompounds in aqueous saline environments, classical molecular dynamics simulations were performed for aqueous solutions of four amino acids (alanine, valine, isoleucine, and 2-aminodecanoic acid), taken as model systems, in the presence of a series of inorganic salts. The MD results reported here provide support for a molecular picture of the salting-in/salting-out mechanism based on the presence/absence of interactions between the anions and the nonpolar moieties of the amino acids. These results are in good qualitative agreement with experimental solubilities and allow for a theoretical interpretation of the available data

Effect of the exchange-correlation potential on the transferability of Bronsted-Evans-Polanyi relationships in heterogeneous catalysis

As more and more accurate density functional methods emerge, the transferability of Bronsted-Evans-Polanyi (BEP) relationships obtained with previous models is an open question. In this work, BEP relationships derived from different density functional theory based calculations are analyzed to answer this question. In particular, BEP relationships linking the activation energy of O-H bond breaking reactions taking place on metallic surfaces with the adsorption energy of the reaction products are chosen as a case study. These relationships are obtained with the widely used Perdew-Wang (PW91) generalized gradient approximation (GGA) exchange-correlation functional and with the more accurate meta-GGA Tao-Perdew Staroverov-Scuseria (TPSS) one. We provide compelling evidence that BEP relationships derived from PW91 and TPSS functionals are essentially coincidental. This finding validates previously published BEP relationships and indicates that the reaction activation energy barrier can be obtained by the determination of the energy reaction descriptor value at the less computationally demanding GGA level; an important aspect to consider in future studies aimed at the computational design of catalysts :with improved characteristics

Methanol dissociation on bimetallic surfaces: validity of the general Bronsted-Evans-Polanyi relationship for O-H bond cleavage

Density functional theory (DFT) calculations were employed to study the dissociation of the O-H bond in methanol on several planar and stepped bimetallic transition metal surfaces, composed of elements showing high or moderate activity towards this reaction, namely, Ni, Rh, Ru, Ir, Pd, Au, Zn and Cu. The activation energies for the O-H bond cleavage were compared with those estimated using a Bronsted-Evans-Polanyi (BEP) relationship for the RO-H bond breakage on pure metal transition surfaces, relating the activation energy for the reaction with the adsorption energies of the reaction products, RO center dot and H-center dot adsorbed on the surface of the catalyst. Furthermore, the average differences between the values of the activation energies calculated with the exhaustive determination of the full reaction path and location of the transition state on each surface model and the activation energies obtained from the BEP relationship with the simple calculation of the adsorption energies of the RO center dot and H-center dot species are similar to 0.14 eV. This suggests that the BEP relationship developed upon the consideration of data for dissociation of the O-H bond in alcohols and water on pure metal surfaces is also valid for a qualitative prediction of the methanol activation energy on bimetallic surfaces

A DFT study of the NO dissociation on gold surfaces doped with transition metals

The NO dissociation on a series of doped gold surfaces (type TMn@Au(111) or TMn@Au(110), with TMn = Ni, Ir, Rh, or Ag and referring n to the number of dopant atoms per unit cell) was investigated through periodic density functional theory calculations. Generally, doping of Au(111) and Au(110) matrices was found to strengthen the interaction with NO species, with the exception of Ag, and was found to increase the energy barrier for dissociation, with the exception of Ni on Au(111). The calculations suggest that the NO dissociation is only possible in the case of the Ir@Au(110) bimetallic surface but only at high temperatures. The increase of the contents of Ir on Au(110) was found to improve significantly the catalytic activity of gold towards the NO dissociation (E-act = similar to 1 eV). Nevertheless, this energy barrier is almost the double of that calculated for NO dissociation on pure Ir(110). However, mixing the two most interesting dopant atoms resulted in a catalyst model of the type Ir@Ni(110) that was found to decrease the energy barrier to values close to those calculated for pure Ir surfaces, i.e., similar to 0.4 eV, and at the same time the dissociation reaction became mildly exothermic. (C) 2013 American Institute of Physics. [http://dx.doi.org/10.1063/1.4790602