Juliana O. S. Giacoppo

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.

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.

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.

Towards the understanding of tetrahydroquinolines action in Aedes aegypti: larvicide or adulticide?

Abstract Aedes aegypti is an important vector of arboviruses such as dengue, yellow fever, chikungunya and Zika. Among the various types of insecticides used to combat this vector, the insect growth regulators have been developed and recommended for control of their larvae. In this work compounds with proven regulatory action, tetrahydroquinolines will be studied. These regulators act on the hormones responsible for the insect development. Ecdysone, one of the main hormones involved in this process has a specific receptor (EcR), where tetrahydroquinolines derivatives can bind, disrupting the normal action of this hormone, because they have structure similar to hormone 20-hydroxyecdysone (20E). In addition, studies show that this class of compounds interacts strongly in the potassium channel activated by calcium (BK channel). Thus, the goal is to study the action of compounds (tetrahydroquinolines) as insecticides and evaluate their larvicidal action (action on the ecdysone receptor) or adulticide (action on the BK channel) through homology modelling techniques, molecular docking and molecular dynamics simulations and aiming to propose a compound that presents both actions (larvicide / adulticide).

Synthesis and in vitro evaluation of leishmanicidal activity of 7-hydroxy-4-phenylcoumarin derivatives

Eight coumarin derivatives (2–8) were synthesized from 7-hydroxy-4-phenylcoumarin 1 and were evaluated for their in vitro leishmanicidal activity against promastigote and amastigote forms of Leishmania amazonensis, as well their toxicity in murine macrophages. Compounds 4 and 7 showed the most significant results against promastigote forms of L. amazonensis. They were at least three-fold more active than 1 and Compound 4 was as effective as Amphotericin B. Compound 4, a 7-O-prenylated derivative, and 7, a tetra-O-acetyl-β-D-glucopyranosyl derivative, presented IC50 values of 21.35 and 10.03 µM against promastigote and IC50 values of 58.10 and 34.93 µM, respectively against amastigote forms. Furthermore, they do not cause toxicity in mammalian or Leishmania cells in vitro. This study shows that these coumarin derivatives are potential prototypes for the development of novel drugs with leishmanicidal activity.