Receptor-dependent four-dimensional quantitative structure-activity relationship (RD-4D-QSAR) studies were applied on a series of 21 peptides reversible inhibitors of Trypanosoma cruzi trypanothione reductase (TR) (Amino Acids, 20, 2001, 145). The RD-4D-QSAR (J Chem Inform Comp Sci, 43, 2003, 1591 approach can evaluate multiple conformations from molecular dynamics simulation and several superposition structure alignments inside a box composed by unitary cubic cells. The descriptors are the occupancy frequency of the atoms types inside the grid cells. We could develop 3D-QSAR models that were highly predictive (q 2 above 0.71). The 3D-QSAR models can be visualized as a spatial map of atom types that are important on the comprehension of the ligand-enzyme interaction mechanism, pointing main pharmacophoric groups and TR subsites described in the literature. We were able also to identify some TR subsites for further development in the drug discovery process against tropical diseases not yet studied.Key words: Chagas' disease, molecular modeling, receptor-dependent four-dimensional quantitative structure-activity relationship, threedimensional quantitative structure-activity relationship, trypanothione reductase The development of computer programs and understanding of the mechanism of drug-receptor interaction allowed to correlate not only the chemical structure-derived two-dimensional (2D) descriptors with the variation of biological response of a series of compounds (e.g., pharmacological activity or toxicity), but also the chemical structure-derived three-dimensional (3D) descriptors. The most popular applied QSAR approach using 3D descriptors, namely 3D-QSAR, was developed by Cramer et al. (3) and called Comparative Molecular Field Analysis (CoMFA). Since the mechanism of drug-receptor interaction is dependent of both, ligand and receptor structures, the knowledge of their 3D structures and conformational behavior in biological media is pivotal. Therefore, although the knowledge of the 3D structure of the receptor and the conformation profile of the ligand was increasing, most of the 3D-QSAR studies did not consider them.Hopfinger et al. (4) in last decades introduced the 'multiple conformation' concept in a new 3D-QSAR approach named 4D-QSAR method. The 4D-QSAR method is able to construct 3D-QSAR models as 3D pharmacophoric maps (4), precisely the type of models one would like to have to complement CoMFA models (3). 4D-QSAR analysis (4) generates their models as a function of alignment for a set of analogues upon both receptor-independent (RI) (4) and receptor-dependent (RD) geometry (5-7). The merits of 4D-QSAR method are in its ability to (8) (i) incorporate ligandconformational flexibility, (ii) explore multiple alignments, (iii) evaluate ligand-embedded pharmacophore groups in so as part of the QSAR models building and optimization process and (iv) propose an 'active' ligand conformation. Because the capability of the 4D-QSAR in exploring large degrees of freedom of both conformational and alignment free...

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Tetragonisca angustula honey was fractioned in a SiO 2 column to furnish three fractions (A-C) in which four hydroxycinnamic acid-Spermidine amides (HCAAs), known as N′, N″, N‴-tris-p-coumaroyl spermidine, N′, N″-dicaffeoyl, N‴-coumaroyl spermidine, N′, N″, N‴-tris-caffeoyl spermidine and N′, N″dicaffeoyl and N‴-feruloyl spermidine were identified in the fractions B and C by electrospray ionization tandem mass spectrometry. A primary culture model previously infected with Neospora caninum (72 h) was used to evaluate the honey fractions (A-C) for two-time intervals: 24 and 72 h. Parasitic reduction ranged from 38% on fraction C (12.5 µg/ml), after 24 h, to 54% and 41% with fractions B and C (25 µg/ml) after 72 h of treatment, respectively. Additionally, HCAAs did not show any cell toxicity for 24 and 72 h. For infected cultures (72 h), the active fractions B (12.5 µg/ml) and C (25 µg/ml) decreased their NO content. In silico studies suggest that HCAAs may affect the parasite's redox pathway and improve the oxidative effect of NO released from infected cells. Here, we presented for the first time, that HCAAs from T. angustula honey have the potential to inhibit the growth of N. caninum protozoa. K E Y W O R D S hydroxycinnamic acid-spermidine amides, immune response, Neospora caninum, nitric oxide, nitrogenous compounds, Tetragonisca angustula honey | 1105 LIMA et al.

Hundreds of millions of people worldwide are affected by Chagas’ disease caused by Trypanosoma cruzi. Since the current treatment lack efficacy, specificity, and suffers from several side‐effects, novel therapeutics are mandatory. Natural products from endophytic fungi have been useful sources of lead compounds. In this study, three lactones isolated from an endophytic strain culture were in silico evaluated for rational guidance of their bioassay screening. All lactones displayed in vitro activity against T. cruzi epimastigote and trypomastigote forms. Notably, the IC50 values of (+)‐phomolactone were lower than benznidazole (0.86 vs. 30.78 μM against epimastigotes and 0.41 vs. 4.88 μM against trypomastigotes). Target‐based studies suggested that lactones displayed their trypanocidal activities due to T. cruzi glyceraldehyde‐3‐phosphate dehydrogenase (TcGAPDH) inhibition, and the binding free energy for all three TcGAPDH‐lactone complexes suggested that (+)‐phomolactone has a lower score value (−3.38), corroborating with IC50 assays. These results highlight the potential of these lactones for further anti‐T. cruzi drug development.

<P>Background: American trypanosomiasis, also known as Chagas disease, is caused by the protozoan Trypanosoma cruzi (T. cruzi) and affects approximately 10 to 12 million, primarily in Latin America. Since its discovery in 1909, there is no effective treatment for its chronic phase, with benzonidazole being the only anti-trypanosoma drug used in Brazil, despite the absence of conclusive evidence to prove its efficacy and safety. Thus, it is necessary to develop new drugs that are more effective and selective against Trypanosoma cruzi. </P><P> Methods: The T. cruzi enzyme Trypanothione Reductase (TcTR) is a validated target for the discovery of new antiprotozoal compounds and we employed the Virtual Screening technique on the database of Nucleus of Bioassays, Biosynthesis and Ecophysiology (NuBBE), aiming to search for new chemical moieties against T. cruzi. From these we selected the 10 best ligand energies interactions and verified their interaction profile with the main TcTR sites through the AuPosSOM server (https://www.biomedicale.univ-paris5.fr/aupossom). </P><P> Results and Conclusion: Finally, we analyzed some pharmacokinetics and toxicological information through the servers Aggregator Advisor (http://advisor.bkslab.org), Pred-hERG 4.0 (http://labmol.com.br/predherg) and pkCSM (http://biosig.unimelb.edu.au/pkcsm/prediction) which we expect will be useful in in vitro preclinical trials.</P>