Structural, thermodynamic and functional studies of human 71 kDa heat shock cognate protein (HSPA8/hHsc70).

Human 71 kDa heat shock cognate protein (HSPA8, also known as Hsc70, Hsp70-8, Hsc71, Hsp71 or Hsp73) is a constitutively expressed chaperone that is critical for cell proteostasis. In the cytosol, HSPA8 plays a pivotal role in folding and refolding, facilitates protein trafficking across membranes and targets proteins for degradation, among other functions. Here, we report an in solution study of recombinant HSPA8 (rHSPA8) using a variety of biophysical and biochemical approaches.

Synthesis and matched molecular pair analysis of covalent reversible inhibitors of the cysteine protease CPB.

Cysteine protease B (CPB) can be targeted by reversible covalent inhibitors that could serve as antileishmanial compounds. Here, sixteen dipeptidyl nitrile derivatives were synthesized, tested against CPB, and analyzed using matched molecular pairs to determine the effects of stereochemistry and p-phenyl substitution on enzyme inhibition. The compound (S)-2-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)-N-(1-cyanocyclopropyl)-3-phenylpropanamide (5) was the most potent CPB inhibitor (pKi = 6.

Novel anti-prostate cancer scaffold identified by the combination of in silico and cell-based assays targeting the PI3K-AKT-mTOR pathway.

Phenotypic assays were performed in prostate cancer cell lines to describe the biological activity of PI3K-AKT-mTOR pathway inhibitors retrieved from the virtual screening initiative. These novel chemicals share in common the aminopyridine scaffold, hitting PC-3 cells in macromolar range, with selectivity index over fibroblast cell lines. Moreover, a preliminary study of the mode of action by flow cytometry assay pointed out that these compounds had a rapamycin-like response for the PI3K-AKT-mTOR pathway modulation.

In silico selection and cell-based characterization of selective and bioactive compounds for androgen-dependent prostate cancer cell.

Prostate cancer is one of the most prevalent types of cancer in male population. It is a hormone driven disease, especially in its initial phase. Hence, androgen deprivation therapy (ADT) is the major chemotherapeutic effort and novel AR inhibitors with improved pharmacological profiles are needed.

Highly predictive hologram QSAR models of nitrile-containing cruzain inhibitors.

The HQSAR, molecular docking, and ROCS were applied to a data-set of 57 cruzain inhibitors. The best HQSAR model (q = .70, r = .

Quantitative structure-retention relationships of flavonoids unraveled by immobilized artificial membrane chromatography.

The pharmacokinetic properties of flavonoids with differing degrees of lipophilicity were investigated using immobilized artificial membranes (IAMs) as the stationary phase in high performance liquid chromatography (HPLC). For each flavonoid compound, we investigated whether the type of column used affected the correlation between the retention factors and the calculated octanol/water partition (log Poct). Three-dimensional (3D) molecular descriptors were calculated from the molecular structure of each compound using i) VolSurf software, ii) the GRID method (computational procedure for determining energetically favorable binding sites in molecules of known structure using a probe for calculating the 3D molecular interaction fields, between the probe and the molecule), and iii) the relationship between partition and molecular structure, analyzed in terms of physicochemical descriptors.

Evaluation of the leishmanicidal and cytotoxic effects of inhibitors for microorganism metabolic pathway enzymes.

Chemotherapy for leishmaniosis a neglected parasitic disease, is based on few drugs, which are toxic and present resistance issues. Efforts for the development of new therapies are essential for the control of leishmaniasis. Metabolic pathway enzymes are promising targets for new drugs against parasites.

Pharmacophore modeling for anti-Chagas drug design using the fragment molecular orbital method.

Background: Chagas disease, caused by the parasite Trypanosoma cruzi, is a neglected tropical disease that causes severe human health problems. To develop a new chemotherapeutic agent for the treatment of Chagas disease, we predicted a pharmacophore model for T. cruzi dihydroorotate dehydrogenase (TcDHODH) by fragment molecular orbital (FMO) calculation for orotate, oxonate, and 43 orotate derivatives.

Conformational differences between the wild type and V30M mutant transthyretin modulate its binding to genistein: implications to tetramer stability and ligand-binding.

Transthyretin (TTR) is a tetrameric beta-sheet-rich transporter protein directly involved in human amyloid diseases. It was recently found that the isoflavone genistein (GEN) potently inhibits TTR amyloid fibril formation (Green et al., 2005) and is therefore a promising candidate for TTR amyloidosis treatment.

Kinetic mechanism and catalysis of Trypanosoma cruzi dihydroorotate dehydrogenase enzyme evaluated by isothermal titration calorimetry.

Trypanosoma cruzi dihydroorotate dehydrogenase (TcDHODH) catalyzes the oxidation of l-dihydroorotate to orotate with concomitant reduction of fumarate to succinate in the de novo pyrimidine biosynthetic pathway. Based on the important need to characterize catalytic mechanism of TcDHODH, we have tailored a protocol to measure TcDHODH kinetic parameters based on isothermal titration calorimetry. Enzymatic assays lead to Michaelis-Menten curves that enable the Michaelis constant (K(M)) and maximum velocity (V(max)) for both of the TcDHODH substrates: dihydroorotate (K(M)=8.

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.

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.

QSAR and molecular modelling studies on B-DNA recognition of minor groove binders.

Aromatic bisamidines have been proved to be efficient compounds against Leishmania spp. and Pneumocystis carinii. Although the mode of action is still not known, these molecules are supposed to be DNA minor groove binders (MGBs).

HEPT derivatives as non-nucleoside inhibitors of HIV-1 reverse transcriptase: QSAR studies agree with the crystal structures.

The interest in the non-nucleoside inhibitors (NNIs) to the reverse transcriptase (RT) as anti-AIDS agents has grown in the last ten years. The compound 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) is the precursor of the most studied class of NNIs, from which hundreds of derivatives have been synthesized and tested. There are at least twelve QSAR studies about the HEPT derivatives as RT inhibitors.