A neural networks study of quinone compounds with trypanocidal activity

This work investigates neural network models for predicting the trypanocidal activity of 28 quinone compounds. Artificial neural networks (ANN), such as multilayer perceptrons (MLP) and Kohonen models, were employed with the aim of modeling the nonlinear relationship between quantum and molecular descriptors and trypanocidal activity. The calculated descriptors and the principal components were used as input to train neural network models to verify the behavior of the nets. The best model for both network models (MLP and Kohonen) was obtained with four descriptors as input. The descriptors were T(5) (torsion angle), QTS1 (sum of absolute values of the atomic charges), VOLS2 (volume of the substituent at region B) and HOMO-1 (energy of the molecular orbital below HOMO). These descriptors provide information on the kind of interaction that occurs between the compounds and the biological receptor. Both neural network models used here can predict the trypanocidal activity of the quinone compounds with good agreement, with low errors in the testing set and a high correctness rate. Thanks to the nonlinear model obtained from the neural network models, we can conclude that electronic and structural properties are important factors in the interaction between quinone compounds that exhibit trypanocidal activity and their biological receptors. The final ANN models should be useful in the design of novel trypanocidal quinones having improved potency.

Docking and molecular dynamics simulation of quinone compounds with trypanocidal activity

In this work, two different docking programs were used, AutoDock and FlexX, which use different types of scoring functions and searching methods. The docking poses of all quinone compounds studied stayed in the same region in the trypanothione reductase. This region is a hydrophobic pocket near to Phe396, Pro398 and Leu399 amino acid residues. The compounds studied displays a higher affinity in trypanothione reductase (TR) than glutathione reductase (GR), since only two out of 28 quinone compounds presented more favorable docking energy in the site of human enzyme. The interaction of quinone compounds with the TR enzyme is in agreement with other studies, which showed different binding sites from the ones formed by cysteines 52 and 58. To verify the results obtained by docking, we carried out a molecular dynamics simulation with the compounds that presented the highest and lowest docking energies. The results showed that the root mean square deviation (RMSD) between the initial and final pose were very small. In addition, the hydrogen bond pattern was conserved along the simulation. In the parasite enzyme, the amino acid residues Leu399, Met400 and Lys402 are replaced in the human enzyme by Met406, Tyr407 and Ala409, respectively. In view of the fact that Leu399 is an amino acid of the Z site, this difference could be explored to design selective inhibitors of TR.

Intraerythrocytic stages of Plasmodium falciparum biosynthesize menaquinone

Herein, we show that intraerythrocytic stages of Plasmodium falciparum have an active pathway for biosynthesis of menaquinone. Kinetic assays confirmed that plasmodial menaquinone acts at least in the electron transport. Similarly to Escherichia coli, we observed increased levels of menaquinone in parasites kept under anaerobic conditions. Additionally, the mycobacterial inhibitor of menaquinone synthesis Ro 48-8071 also suppressed menaquinone biosynthesis and growth of parasites, although off-targets may play a role in this growth-inhibitory effect. Due to its absence in humans, the menaquinone biosynthesis can be considered an important drug target for malaria. (c) 2010 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

Biomimetic biosensor based on lipidic layers containing tyrosinase and lutetium bisphthalocyanine for the detection of antioxidants

This paper describes the preparation of a biomimetic Langmuir-Blodgett film of tyrosinase incorporated in a lipidic layer and the use of lutetium bisphthalocyanine as an electron mediator for the voltammetric detection of phenol derivatives, which include one monophenol (vanillic acid), two diphenols (catechol and caffeic acid) and two triphenols (gallic acid and pyrogallol). The first redox process of the voltammetric responses is associated with the reduction of the enzymatically formed o-quinone and is favoured by the lutetium bisphthalocyanine because significant signal amplification is observed, while the second is associated with the electrochemical oxidation of the antioxidant and occurs at lower potentials in the presence of an electron mediator. The biosensor shows low detection limit (1.98 x 10(-6)-27.49 x 10(-6) M), good reproducibility, and high affinity to antioxidants (Km in the range of 62.31-144.87 mu M). The excellent functionality of the enzyme obtained using a biomimetic immobilisation method, the selectivity afforded by enzyme catalysis, the signal enhancement caused by the lutetium bisphthalocyanine mediator and the increased selectivity of the curves due to the occurrence of two redox processes make these sensors exceptionally suitable for the detection of phenolic compounds. (C) 2010 Elsevier B.V. All rights reserved.

Withanolides from Aureliana fasciculata var. fasciculata

In the first phytochemical study of the Aureliana genus (Solanaceae), two new withanolides, 1 and 2, together with two known sterols, were isolated from the MeOH extract of the leaves of Aureliana fasciculata var. fasciculata. The structures were established as (4S,22R)-16 alpha-acetoxy-5 beta,6 beta-epoxy-4 beta,17 alpha-dihydroxy-1-oxowitha-2,24-dienolide (aurelianolide A) and (4S,22R)-16 alpha-acetoxy-4 beta,17 alpha-dihydroxy-1-oxowitha-2,5,24-trienolide (aurelianolide B). The new compounds possessed the unusual 16 alpha,17 alpha-dioxygenated group and were fully characterized by spectroscopic techniques, including (1)H- and (13)C-NMR (DEPT), as well as 2D-NMR (HMBC, HMQC, (1)H, (1)H-COSY, NOESY) experiments, and HR-MS.

Spectroscopic investigation of the interactions between emeraldine base polyaniline and Eu(III) ions

The interactions of emeraldine base form of polyaniline (EB-PANI) and Eu(III) ions in 1-methyl-2-pyrrolidinone (NMP) solution and in films have been investigated by UV-vis-NIR, resonance Raman. luminescence and electron paramagnetic resonance (EPR) spectroscopies. These spectroscopic techniques allowed to characterize quinone and semiquinone segments in the polymeric chains. and the oxidation state of europium ions in Eu-PANI samples. For high values of Eu(III)/N molar ratio (24/1) the presence of a weak polaronic absorption band at 980 nm in UV-vis-NIR spectrum and the observation of bands at 1330 and 1378 (nu(center dot)(C-N+)) cm(-1) due to emeraldine salt in the Raman spectrum at 1064 nm indicate a low doping degree. Oxidation of EB-PANI to pernigraniline base (PB-PANI) occurs in diluted solutions. The experimental data showed that the solvent plays an important role on the nature of formed species. The narrow EPR signal at g = 2.006 (line width 8G) confirms the presence of PANI radical cations in Eu-PANI film. The absence of broad signal characteristic of Eu(II) in EPR spectrum suggested that europium ions are primarily at Eu(III) oxidation state. The luminescence spectra of Eu-PANI film presented emission bands at 405 and 418 nm assigned to PANI moieties and bands at 594,615 and 701 nm assigned to (5)D(0) -> (7)F(J) (J = 1, 2 and 4, respectively) transitions of Eu(III). EPR and photoluminescence data confirm that europium ions are mainly in Eu(III) oxidation state in Eu(III)/PANI films. (C) 2008 Elsevier B.V. All rights reserved.