Target Fisher: A Consensus Structure-Based Target Prediction Tool, and its Application in the Discovery of Selective MAO-B Inhibitors.

In this work we introduce Target Fisher, a consensus structure-based target prediction tool that integrates molecular docking and machine learning with the aim to aid in the identification of potential biological targets and the optimization of the use of bioassays. Target Fisher uses per-residue energy decomposition profiles extracted from docking poses as fingerprints to train target-specific machine learning models. It provides predictions for a curated set of 37 protein targets, covering a diverse range of biological entities, and offers a user-friendly interface accessible via a web server (https://gqc.

Host cell cAMP-Epac-Rap1b pathway inhibition by hawthorn extract as a potential target against infection.

Although the two drugs currently available for the treatment of Chagas disease, Benznidazole and Nifurtimox, have proven to be effective in the acute phase of the disease, the 60-90-day treatment leads to high toxicity and unwanted side effects, presenting, in addition, a low efficacy in the chronic phase of the disease. For this reason, new therapies that are more effective are needed. In this regard, we have recently shown that the inhibition of the Epac-Rap1b pathway suppressed the cAMP-mediated host cell invasion by .

Screening of Protein-Protein Interaction Modulators Using BRET-Based Technology.

Protein-protein interactions (PPIs) play central roles in most molecular mechanisms underlying cellular and biological processes. Within the methods developed to study PPIs is bioluminescence resonance energy transfer (BRET). Taking advantage of this technique, we have set a BRET-based assay that enables the screening of modulators of essential PPIs for Trypanosoma cruzi survival.

Antiparasitic Derivatives of the Furoquinoline Alkaloids Kokusaginine And Flindersiamine.

We report the synthesis of 16 new compounds obtained from kokusaginine and flindersiamine, the main alkaloids isolated from the bark of Balfourodendron riedelianum. The activity of the compounds against axenic cultures of Trypanosoma cruzi epimastigtotes and trypomastigotes, as well as intracellular amastigotes, is described, together with their cytotoxic activity against three different human cell lines. The synthetic strategy for the preparation of the new compounds was based on the reactivity at the C4 position of the furoquinoline core towards nucleophiles.

Optimization of a Bioluminescence Resonance Energy Transfer-Based Assay for Screening of Trypanosoma cruzi Protein/Protein Interaction Inhibitors.

Chagas disease, a parasitic disease caused by Trypanosoma cruzi, is a major public health burden in poor rural populations of Central and South America and a serious emerging threat outside the endemic region, since the number of infections in non-endemic countries continues to rise. In order to develop more efficient anti-trypanosomal treatments to replace the outdated therapies, new molecular targets need to be explored and new drugs discovered. Trypanosoma cruzi has distinctive structural and functional characteristics with respect to the human host.

Synthesis and antifungal activity of bile acid-derived oxazoles.

Peracetylated bile acids (1a-g) were used as starting materials for the preparation of fourteen new derivatives bearing an oxazole moiety in their side chain (6a-g, 8a-g). The key step for the synthetic path was a Dakin-West reaction followed by a Robinson-Gabriel cyclodehydration. A simpler model oxazole (12) was also synthesized.

Antifungal terpenoids from Hyalis argentea var. latisquama.

A detailed chemical study of the aerial parts and rhizomes of Hyalis argentea var. latisquama yielded a variety of sesqui- and diterpenes. In total, 26 compounds were isolated and identified, of which four are new, namely, two ent-kaurenes (1 and 2), a diterpene lactone (3), and a lindenanolide (4).

Antioxidant neolignans from Cordia americana.

Five new neolignans with a bicyclo[2.2.2]octene framework were isolated from an ethanolic extract of the bark of Cordia americana.

Metal binding properties and structure of a type III metallothionein from the metal hyperaccumulator plant Noccaea caerulescens.

Metallothioneins (MT) are low molecular weight proteins with cysteine-rich sequences that bind heavy metals with remarkably high affinities. Plant MTs differ from animal ones by a peculiar amino acid sequence organization consisting of two short Cys-rich terminal domains (containing from 4 to 8 Cys each) linked by a Cys free region of about 30 residues. In contrast with the current knowledge on the 3D structure of animal MTs, there is a striking lack of structural data on plant MTs.

Cytotoxic terpenoids from Nardophyllum bryoides.

The investigation of the ethanol extract of fresh aerial parts of the Patagonian shrub Nardophyllum bryoides collected in the province of Chubut, Argentina, yielded eleven terpenoids. These include: three seco-ent-halimane diterpenoids (1-3), two ent-halimanes (4-5) and six pentacyclic oleanane and ursane triterpenoids (6-11). Four of these compounds (2, 6, 8 and 11) are hitherto unknown, while two others (1 and 4) have been previously reported but only as synthetic products.