Resumo dos 5 artigos mais relevantes do grupo

Merlino, A.; Benitez, D.; Campillo, N. E.; Paéz, J. A.; Tinoco, L. W.; González, M.; Cerecetto, H. Amidines bearing benzofuroxan or benzimidazole 1,3-dioxide core scaffolds as Trypanosoma cruzi-inhibitors: structural basis for their interactions with cruzipain. Med. Chem. Commun., 2012, 3, 90.
Abstract: Trypanosoma cruzi, the causative agent of Chagas’ disease, affects tens of millions of South Americans. One of the most studied T. cruzi-biomolecules as a target for drug development is cruzipain, an essential cysteine proteinase of this parasite. Some of our recent studies identified amidine containing benzofuroxans as hit compounds for cruzipain inhibition with trypanosomicidal activities. Experimental and theoretical studies inspired us to modify these compounds by maintaining the amidine motif and using benzofuroxan and benzimidazole 1,3-dioxide systems as core scaffolds in order to obtain better cruzipain inhibitors. The new amidines had excellent trypanosomicidal activity, with good selectivity indexes, but without improved cruzipain-inhibitory activities compared with the parent compounds. The interaction of amidines with cruzipain has been investigated through a combined NMR -T1-differences, DOSY, and STD- and molecular docking approaches. Despite the low cruzipain-inhibition ability, our data suggest that these designed compounds have relevant structural features, i.e. aromatic groups and protonated moieties with stabilizing complex ability using stacking and electrostatic interactions, respectively, that bind reversibly to cruzipain.

Alvarez, G.; Aguirre-Lopez, B.; Cabrera, N.; Marins, E. B.; Tinoco, L. W.; Batthyany, C. I.; Gomez-Puyou, M. T.; Puyou, A. G.; Perez-Montfort, R.; Cerecetto, H.; Gonzalez, M. 1,2,4-thiadiazol-5(4H)-ones: a new class of selective inhibitors of Trypanosoma cruzi triosephosphate isomerase. Study of the mechanism of inhibition. Journal of Enzyme Inhibition and Medicinal Chemistry, 2012; Early Online: 1–9
Abstract: Context: Triosephosphate isomerase (TIM) is a ubiquitous enzyme that has been targeted for the discovery of small molecular weight compounds with potential use against Trypanosoma cruzi, the causative agent of Chagas disease. We have identified a new selective inhibitor chemotype of TIM from T. cruzi (TcTIM), 1,2,4-thiadiazol-5(4H)-one.
Objective: Study the mechanism of TcTIM inhibition by a 1,2,4-thiadiazol derivative.
Methods: We performed the biochemical characterization of the interaction of the 1,2,4-thiadiazol derivative with the wild-type and mutant TcTIMs, using DOSY-NMR and MS experiments. Studies of T. cruzi growth inhibition were additionally carried out.
Results and conclusion: At low micromolar concentrations, the compound induces highly selective irreversible inactivation of TcTIM through non-covalent binding. Our studies indicate that it interferes with the association of the two monomers of the dimeric enzyme. We also show that it inhibits T. cruzi growth in culture.
Keywords: Chagas disease, TcTIM, thiadiazol, inactivation mechanism

Rennó, M. N., França, T. C. C.; Nico, D.; Palatnik-de-Sousa, C. B.; Tinoco, L. W.; Figueroa-Villar, J. D. Kinetics and docking studies of two potential new inhibitors of the nucleoside hydrolase from Leishmania donovani. European Journal of Medicinal Chemistry, 2012, 1-7.
Abstract: In this study the recombinant enzyme nucleoside hydrolase of Leishmania donovani (rLdNH) was expressed in Escherichia coli in connection with maltose binding protein (MBP). The rLdNHeMBP showed efficient a significant in vitro activity with inosine as substrate. From the coupled reaction with xanthine oxidase (XO) it was possible to determine the kinetic constants of rLdNHeMBP as KM (434 ± 109 mM) and Vmax (0.20 ± 0.02 mM). In addition, two nucleoside analogs (compounds 1 and 2) were tested as prototypes of rLdNH inhibitors. These compounds presented high affinity for the enzyme with Ki values of 1.6 ± 0.2 and 17.0 ± 2.1 mM, respectively, as well as 271 and 26 folds higher than the affinity constant found for inosine. We also determined the type of enzyme inhibition, using double-reciprocal plot for these two compounds and the results confirmed a competitive inhibition. Additional docking studies showed the binding manner of compounds 1 and 2 inside the active site of LdNH revealing the essential residues for an effective inhibition. These results confirm that compounds 1 and 2 are strong rLdNHeMBP inhibitors.

Figueroa-Villar, J. D. and Tinoco, L. W. Spin-Lattice Relaxation Time in Drug Discovery and Design. Current Topics in Medicinal Chemistry, 2009, 9, 811-823.
Abstract: NMR is one of the most powerful techniques for ligand-biomolecule interaction studies and drug screening and design. There are several methods that are strongly used, including chemical shift perturbation (CSP), saturation transfer difference (STD) and diffusion coefficients. However, one of the most useful and easy to apply NMR parameters in medicinal chemistry studies is the spin-lattice relaxation data, which can be employed to investigate the strength and topology of intermolecular interactions, such as drug-drug, drug-protein, drug-DNA, drug-micelle (or vesicle) and biomolecule-biomolecule interactions. This review deals with the newest applications of T1 in different studies of interest for drug design and evaluation.

Tinoco, L. W.; Gomes-Neto, F. G.; Valente, A. P.; Almeida, F. C. L. Effect of micelle interface on the binding of anticoccidial PW2 peptide. J. Biomol. NMR, 2007, 39,315–322.
Abstract: PW2 is an anticoccidial peptide active against Eimeria acervulina and Eimeria tenella. We determined the structure of PW2 in dodecylphosphocholine micelles. The structure showed two distinct regions: an amphipathic N-terminal 310 helix and an aromatic region containing WWR interface-binding motif. The aromatic region acted as a scaffold of the protein in the interface and shared the same structure in both DPC and SDS micelles. N-terminal helix interacted with DPC but not with SDS interface. Chemical shift change was slow when SDS was added to PW2 in DPC and fast when DPC was added to PW2 in SDS, indicating that interaction with DPC micelles was kinetically more stable than with SDS micelles. Also, DPC interface was able to accommodate PW2, but it maintained the conformational arrangement in the aromatic region observed for SDS micelles. This behavior, which is different from that observed for other antimicrobial peptides with WWR motif, may be associated with the absence ofPW2 antibacterial activity and its selectivity for Eimeria parasites.