Publications

Abstract Nelfinavir (Viracept, Pfizer), and Amprenavir (Ageneraze(R), GlaxoSmithKline) are potent bioavailable inhibitors of the enzyme Protease (PR) of the Human Immunodeficiency Virus-1 (HIV-1), which have been developed by consistent structure-based drug design projects, and have been approved worldwide for the treatment of HIV infected patients. They act as competitive inhibitors, and tightly bind the active site of PR with high shape and electrostatic potential complementarily. However, the virus has shown the ability of fixating mutations which decrease the affinity of the antiretrovirals for the binding pocket of PR, although at the cost of decreasing (but to a minor extent) the affinity for the substrate. The consequent appearance of drug resistance compromised the long term efficacy of the drug. In this work we have extended such structure based drug design effort with computational methodologies, by performing very small substitutions in the inhibitors, directed at interacting with the most conserved amino acids. It is not possible to mutate the latter, at the cost of making the enzyme catalytically inactive. We show with a set of examples that significant increases in affinity can still be achieved without changing the overall structure, molecular mass and hydrophobicity of the inhibitors, thus preserving their very favourable ADME properties.

Abstract The standard (p degrees = 0.1 MPa) molar enthalpies of formation of crystalline 2,3,5-trimethylpyrazine-1,4-dioxide and 2,3,5,6-tetramethylpyrazine-1,4-dioxide were measured, at T = 298.15 K, by static bomb calorimetry and the standard molar enthalpies of sublimation, at T = 298.15 K, were obtained from Calvet microcalorimetric measurements. These values were used to derive the respective standard molar enthalpies of formation in gaseous phase. The mean N-O bond dissociation enthalpy has been calculated for both compounds. (c) 2006 Published by Elsevier B.V.

Abstract DFT calculations have been performed to investigate the effect of several different substituents on the N-O bond dissociation enthalpies of 2-substituted-quinoxaline-1,4-dioxides. Further, the influence of electron and proton affinities and also of N-O bond dissociation enthalpies on the antitumor activity of selected compounds is analyzed. In agreement with experimental data, the calculations suggest that Tirapazamine is more active than Quindoxin due to a much easier reduction and protonation of the former species accompanied by a weaker N-OH bond.

Abstract Computer simulations can be very useful in teaching chemical equilibrium like salt solubility. As a computer generated animation, Computer Simulations of Salt Solubility compares pair of compounds chosen like NaCL and CaCo3. The computer program simulates in a qualitative manner, the "before" and "after" states for the dissolution of equal amounts of NaCl and CaCO3 in identical amounts of water. Total entropy increases in the case of NaCl due to the increase of configurational disorder of salt ions. However, in the case of CaCO3, an identical effect is offset by the decrease of mobility of the water molecules associated with the dipositive calcium ion. Ion salvation is less relevant both in the case of the monocharged ions Na+ and Cl- and in the case of large ion CO3 2-. Same procedure can be done for MgCO3 and MgSO4 simulation.

Abstract Computer simulations of salt solubility used a Java applet and Web browser to present an animated illustration of differences in the solubility of salts. The simulation provides an animated, visual interpretation of the different solubilities of related salts based on simple entropy changes associated with dissolution: configurational disorder and thermal disorder. Pairs of compounds chosen for the animation are NaCl/CaCO3 and MgCO3/MgSO4. In the former case, both dissolution are almost athermic, hence the major differences are in configurational disorder and solvation effects. In the latter pair, the major difference lies in thermal disorder, as the dissolution of magnesium sulfate is quite exothermic. Changes in total entropy and in its components are represented qualitatively in bar graphs.

Abstract Two-way data structures were obtained by acquiring UV-vis spectra as function of the time of the alkaline hydrolysis reaction of the antihypertensor Nifedipine in dimethylsulfoxide (DMSO). Sets of three-way data structures were obtained from the analysis of solutions with different concentrations of Nifedipine generated by standard additions to DMSO, Nifedipine standard and a pharmaceutical formulation. PARAFAC and PARAFAC2 methods were used in the analysis of these multi-way data structures and calibration models were developed for Nifedipine quantification in pharmaceutical formulations. For all the three-way data structures a better model fit was found with the PARAFAC2 suggesting that the experimental data sets have deviations from trilinearity. The best concentrations estimations were found with the PARAFAC2 model in the analysis of a [concentration x time (s) x wavelength (nm)] three-way data structure which allows the quantification of Nifedipine in pharmaceutical formulations.

Abstract (Figure Presented) Sharp practice: A water/n-octanol interface can be formed at the tip of a very short and sharp nanopipette, and can be polarized externally (see picture). This interface has been used to investigate various ion-transfer processes and evaluate partition coefficients for ionizable species. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.

Abstract The coordination chemistry of 2,8-dithia[9],(2,9)-1,10-phenanthrolinophane (L) towards transition and post-transition metal ions such as Cu(II), Cu(I), Cd(II), Co(II), Ni(II), Pb(II) and Zn(II) was studied at the polarized water/1,2-dichloroethane interface by cyclic voltammetry. The dependence of the half-wave transfer potential on the ligand and metal concentrations was used to formulate the stoichiometry, and to evaluate the association constants of the complexes formed between L and Pb(II).

Abstract A catanionic surfactant consists of paired oppositely charged surfactant ions, acting as counterions to each other. In this work, a series of catanionic surfactants with the cationic quaternary ammonium group and anionic sulfate group, with variation of chain length and number of chains, have been synthesized. The results of the Langmuir pressure-area isotherms, for compression and cycles of compression-decompression, have been used to discuss the effect of length and number of hydrophobic chains on the phase behavior and molecular organization of the spread catanionic film. The molecular desorption from the catanionic film, involving either dissolution of the catanionic surfactant or desorption of the organic counterion (short chain ionic moiety), is critically discussed.

Abstract An experimental setup to study the pH dependence of standard ion-transfer potentials at the water/NPOE interface is presented. The system is composed of a microhole generated by laser photoablation in a 12-mu m polyethylene terephthalate film, the aqueous phase consisting of a commercial immobilized pH gradient gel reswelled in electrolyte solution and a droplet of organic solution. Two electrodes are used, an Ag/AgCl aqueous electrode and an Ag/AgTPBCl organic electrode. This setup is applied to the study of two ionizable compounds (pyridine, 2,4-dinitrophenol). Thermodynamic parameters such as the standard transfer potential, the Gibbs energy of transfer, and the partition coefficients of the ionized forms as well as the neutral forms of these drug compounds are evaluated by differential pulse voltammetry. The data obtained are summarized in ionic partition diagrams, which are a useful tool for predicting and interpreting the transfer behavior of ionized drugs at the liquid/liquid interfaces mimicking the biological membranes.