Daiana T. Mancini

Molecular modeling and in vitro reactivation study between the oxime BI-6 and acetylcholinesterase inhibited by different nerve agents.

Nerve agents are organophosphates acting as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine and, consequently, the termination of the transmission of nerve impulses. The inhibition of AChE by an organophosphate can be reversed by a nucleophilic agent able to dephosphorylate a serine residue in the active site of AChE. In this sense, the oximes are compounds capable of removing the nerve agent and reactivate the enzyme. Here, we have applied a methodology involving theoretical docking and Quantum Mechanics/Molecular Mechanics, using the softwares Molegro® and Spartan®, to evaluate the kinetic constants of reactivation and the interactions of the oxime BI-6 with AChE inhibited by different organophosphorus compounds in comparison to in vitro data. Results confirm that this method is suitable for the prediction of kinetic and thermodynamic parameters of oximes, which may be useful in the design and selection of new and more effective oximes.

New approaches to the development of anti-protozoan drug candidates: a review of patents

Protozoan infections are parasitic diseases that affect hundreds of millions of people worldwide, but have been largely neglected for drug development because they affect poor people in poor regions of the world. Most of the current drugs used to treat these diseases are decades old and have many limitations, including the emergence of drug resistance. This review will focus on the most recent developments, from 2001 to 2008, published in the field of patents and publications, paying particular attention to promising compounds acting against trypanosomiasis, leishmaniasis, malaria, toxoplasmosis, amebiasis, giardiasis, balantidiasis and pneumocystosis, their chemistry and biological evaluation, and to new chemical and pharmaceutical processes.

Molecular modeling of the Toxoplasma gondii adenosine kinase inhibitors

Toxoplasma gondii is the most common cause of secondary central nervous system infection in immunocompromised people such as AIDS patients. Since purine salvage is essential for T. gondii and other parasitic protozoa, inhibition of its salvage pathway, by blocking adenosine kinase (EC 2.7.1.20), the main responsible for the metabolism of adenosine (purine nucleoside) can block the parasite growth. Having this in mind, four-dimensional quantitative structure–activity relationship (4D-QSAR) analysis was applied to a series of 41 inhibitors of T. gondii adenosine kinase. Optimized 4D-QSAR models were constructed by genetic algorithm (GA) optimization and partial least squares (PLS) fitting, and evaluated by the leave-one-out cross-validation method. Moreover, we have used docking approaches to study the binding orientations and predict the interaction energies of some benzyladenosines with adenosine kinase.

Molecular aspects of the reactivation process of acetylcholinesterase inhibited by cyclosarin

®® para avaliar as constantes cineticas de associacao e reativacao de oximas, em relacao a resultados in vitro previamente reportados na literatura. Como observado antes, os resultados mostraram boa correlacao entre as energias livres teoricas de ligacao das oximas e os dados experimentais, corroborando a metodologia como adequada para a predicao de parâmetros cineticos e termodinâmicos, os quais podem ser uteis para o planejamento e selecao de novas e mais efetivas oximas. In this work we applied a theoretical methodology developed in a former work, using the Molegro ® and Spartan ® softwares, to evaluate the association and kinetic reactivation constants of oximes, facing in vitro data previously reported in the literature. As reported before, results showed a good agreement between the theoretical binding free energies of the oximes and experimental data, corroborating the methodology as suitable for the prediction of kinetic and thermodynamic parameters that might be helpful for the design and selection of new and more effective oximes.

Asymmetric biocatalysis of the nerve agent VX by human serum paraoxonase 1: molecular docking and reaction mechanism calculations

Organophosphorus compounds have been employed in agricultural activity for a long time, causing serious public health problems. Due to their toxic properties, these compounds have also been used as chemical weapons. In view of this scenario, the catalytic degradation and the development of bioremediation processes of organophosphorus compounds have been of wide interest. Among several enzymes capable of degrading organophosphorus compounds, the human serum paraoxonase 1 has shown good potential for this purpose. To evaluate the interaction mode between the human serum paraoxonase 1 (wild-type and mutants) enzymes and the VX compound, one of the most toxic organophosphorus compounds known, molecular docking calculations were conducted. In addition, seeking to analyze the reaction pathway and the stereochemistry preference by human serum paraoxonase 1 and the Rp and Sp enantiomers of VX, quantum mechanical/molecular mechanics calculations were performed. Our theoretical findings put in evidence that the wild-type and mutant human serum paraoxonase 1 enzymes strongly interact with VX. Moreover, with the quantum mechanical/molecular mechanics study, we observed that the human serum paraoxonase 1 preferentially degrades one enantiomer in relation to the other. The current results indicate key points for designing new, more efficient mutant human serum paraoxonase 1 enzymes for VX degradation.

99Tc NMR as a promising technique for structural investigation of biomolecules: theoretical studies on the solvent and thermal effects of phenylbenzothiazole complex

The phenylbenzothiazole compounds show antitumor properties and are highly selective. In this paper, the 99Tc chemical shifts based on the (99mTc)(CO)3(NNO) complex conjugated to the antitumor agent 2‐(4′‐aminophenyl)benzothiazole are reported. Thermal and solvent effects were studied computationally by quantum‐chemical methods, using the density functional theory (DFT) (DFT level BPW91/aug‐cc‐pVTZ for the Tc and BPW91/IGLO‐II for the other atoms) to compute the NMR parameters for the complex. We have calculated the 99Tc NMR chemical shifts of the complex in gas phase and solution using different solvation models (polarizable continuum model and explicit solvation). To evaluate the thermal effect, molecular dynamics simulations were carried, using the atom‐centered density matrix propagation method at the DFT level (BP86/LanL2dz). The results highlight that the 99Tc NMR spectroscopy can be a promising technique for structural investigation of biomolecules, at the molecular level, in different environments. Copyright

Theoretical spectroscopic studies and identification of metal-citrate (Cd and Pb) complexes by ESI-MS in aqueous solution

The combined use of ESI-MS, FTIR-ATR and theoretical calculations for the determination of metal-citrate (metal=Cd and Pb) structures are reported. Mass spectrometry allowed to determine the stoichiometry 1:1 and 2:1 of the complexes, corroborating the theoretical calculations. The species found in the ratio 2:1 had their molecular structures readjusted, since the deprotonation of citric acid differed from what was simulated. The calculations of thermodynamic stability (ΔH(0)(aq.)) for the complexes obtained by B3LYP/LANL2DZ were more exoenergetic than those found by PM6. However, for both methods, the stability of the complexes follows a trend, that is, the lowest-energy isomers in PM6 are also the most stable in B3LYP/LANL2DZ. The infrared analysis suggested that carboxyl groups are complexation sites and hydrogen bonds can help in the stability of the complexes. The vibrational frequencies in B3LYP/LANL2DZ had a good correlation with the experimental infrared results.

Molecular modeling toward selective inhibitors of dihydrofolate reductase from the biological warfare agent Bacillus anthracis

In the present work, we applied docking and molecular dynamics techniques to study 11 compounds inside the enzymes dihydrofolate reductase (DHFR) from the biological warfare agent Bacillus anthracis (BaDHFR) and Homo sapiens sapiens (HssDHFR). Six of these compounds were selected for a study with the mutant BaF96IDHFR. Our results corroborated with experimental data and allowed the proposition of a new molecule with potential activity and better selectivity for BaDHFR.

Structural determination of Cu and Fe-Citrate complexes: theoretical investigation and analysis by ESI-MS

The combined use of ESI-MS (electrospray ionization-mass spectrometry) and theoretical calculations for the determination of citrate:metal (metal=Cu and Fe) structures are reported. Mass spectrometry allowed to determine the stoichiometry 1:1 and 2:1 of the complexes, corroborating the theoretical calculations. The species found in the ratio 2:1 had their calculated structures readjusted, from what was originally simulated, since the deprotonation of citric acid differed from what was before simulated. The thermodynamic stability (ΔH(aq.)(0)) of the complexes optimized at the B3LYP/LANL2DZ level was more exoenergetic than for the complexes found by the PM6 semi-empirical method.

Bonding, Structure, and Stability of Clusters: Some Surprising Results from an Experimental and Theoretical Investigation in Gas Phase

Structure and stability of clusters in the ground state were analyzed at the theoretical and experimental levels. Our experimental and theoretical findings showed that the clusters in gas phase tend to form mainly planar rings of four members. The symmetry and the small dipole moment in these specific configurations suggested that their stability could be associated with an alignment of the water molecules, maximizing attractive electrostatic interactions caused by changes in the charge distribution of the clusters.