Uncovering false positives on a virtual screening search for cruzain inhibitors

Some unexpected promiscuous inhibitors were observed in a virtual screening protocol applied to select cruzain inhibitors from the ZINC database. Physical-chemical and pharmacophore model filters were used to reduce the database size. The selected compounds were docked into the cruzain active site. Six hit compounds were tested as inhibitors. Although the compounds were designed to be nucleophilically attacked by the catalytic cysteine of cruzain, three of them showed typical promiscuous behavior, revealing that false positives are a prevalent concern in VS programs. (C) 2007 Elsevier Ltd. All rights reserved.

Understanding the Effect of Adsorption Geometry over Substrate Selectivity in the Surface-Enhanced Raman Scattering Spectra of Simazine and Atrazine

This paper studies the selectivity of Well-defined Au and Ag nanostructures as substrates for the SERS, (surface-enhanced Raman scattering) detection of simazine (6-chloro-N,N`-diethyl-1,3,5-triazine-2,4-diamine) and atrazine (6-chloro-N-ethyl-N`-isopropyl-1,3,5-triazine-2,4-diamine). Our data showed that simazine and atrazine displayed similar SERS spectra when the Au was employed as substrate. Conversely, distinct SERS signatures were obtained upon the utilization of Ag substrates. Density functional theory (DFT) calculations and vibrational assignments suggested that, while simazine and atrazine adsorbed on Au via the N3 position of the triazine ring, simazine adsorbed on Ag via N3 and atrazine via N5. The results presented herein demonstrated that the adsorption geometry of analyte molecules can play a central role over substrate selectivity in SERS, which is particularly important in applications involving ultrasensitive analysis of mixtures containing structurally similar molecules.

Pt monolayer electrocatalysts for O-2 reduction: PdCo/C substrate-induced activity in alkaline media

We measured the activity of electrocatalysts, comprising Pt monolayers deposited on PdCo/C substrates with several Pd/Co atomic ratios, in the oxygen reduction reaction in alkaline solutions. The PdCo/C substrates have a core-shell structure wherein the Pd atoms are segregated at the particle`s surface. The electrochemical measurements were carried out using an ultrathin film rotating disk-ring electrode. Electrocatalytic activity for the O-2 reduction evaluated from the Tafel plots or mass activities was higher for Pt monolayers on PdCo/C compared to Pt/C for all atomic Pd/Co ratios we used. We ascribed the enhanced activity of these Pt monolayers to a lowering of the bond strength of oxygenated intermediates on Pt atoms facilitated by changes in the 5d-band reactivity of Pt. Density functional theory calculations also revealed a decline in the strength of PtOH adsorption due to electronic interaction between the Pt and Pd atoms. We demonstrated that very active O-2 reduction electrocatalysts can be devised containing only a monolayer Pt and a very small amount of Pd alloyed with Co in the substrate.

Cassava wastewater as a substrate for the simultaneous production of rhamnolipids and polyhydroxyalkanoates by Pseudomonas aeruginosa

Glycerol, cassava wastewater (CW), waste cooking oil and CW with waste frying oils were evaluated as alternative low-cost carbon substrates for the production of rhamnolipids and polyhydroxyalkanoates (PHAs) by various Pseudomonas aeruginosa strains. The polymers and surfactants produced were characterized by gas chromatography-mass spectrophotometry (MS) and by high-performance liquid chromatography-MS, and their composition was found to vary with the carbon source and the strain used in the fermentation. The best overall production of rhamnolipids and PHAs was obtained with CW with frying oil as the carbon source, with PHA production corresponding to 39% of the cell dry weight and rhamnolipid production being 660 mg l(-1). Under these conditions, the surface tension of the culture decreased to 30 mN m(-1), and the critical micelle concentration was 26.5 mg l(-1). It would appear that CW with frying oil has the highest potential as an alternative substrate, and its use may contribute to a reduction in the overall environmental impact generated by discarding such residues.

Integration of Ligand- and Target-Based Virtual Screening for the Discovery of Cruzain Inhibitors

A myriad of methods are available for virtual screening of small organic compound databases. In this study we have successfully applied a quantitative model of consensus measurements, using a combination of 3D similarity searches (ROCS and EON), Hologram Quantitative Structure Activity Relationships (HQSAR) and docking (FRED, FlexX, Glide and AutoDock Vina), to retrieve cruzain inhibitors from collected databases. All methods were assessed individually and then combined in a Ligand-Based Virtual Screening (LBVS) and Target-Based Virtual Screening (TBVS) consensus scoring, using Receiving Operating Characteristic (ROC) curves to evaluate their performance. Three consensus strategies were used: scaled-rank-by-number, rank-by-rank and rank-by-vote, with the most thriving the scaled-rank-by-number strategy, considering that the stiff ROC curve appeared to be satisfactory in every way to indicate a higher enrichment power at early retrieval of active compounds from the database. The ligand-based method provided access to a robust and predictive HQSAR model that was developed to show superior discrimination between active and inactive compounds, which was also better than ROCS and EON procedures. Overall, the integration of fast computational techniques based on ligand and target structures resulted in a more efficient retrieval of cruzain inhibitors with desired pharmacological profiles that may be useful to advance the discovery of new trypanocidal agents.