Dibenzosuberyl substituted polyamines and analogs of clomipramine as effective inhibitors of trypanothione reductase; molecular docking, and assessment of trypanocidal activities

O’Sullivan, Mary C.; Durham, Timothy B.; Valdes, Hannah E.; Dauer, Kelly L.; Karney, Nicholas J.; Forrestel, Andrew C.; Bacchi, Cyrus J.; Baker, Jerome F.

doi:10.1016/j.bmc.2015.01.018

Cited by 23 publications

(8 citation statements)

References 125 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This indicates that the presence of hydrogen atoms between the ring planes that form hydrogen bonds, significantly influence the geometries and strengthen interactions between two parallel rings. In systems 1 and 2, there are double bifurcated intermolecular hydrogen bonds, NH-N and NH-S in the case of thiosemicarbazide (1) and NH-N and NH-O in case of semicarbazide (2) (Figure 9), which contribute to the strength of the interactions.…”

Section: Discussionmentioning

confidence: 99%

Very Strong Parallel Interactions Between Two Saturated Acyclic Groups Closed with Intramolecular Hydrogen Bonds Forming Hydrogen-Bridged Rings

2016

View full text Add to dashboard Cite

Saturated acyclic four-atom groups closed with a classic intramolecular hydrogen bond, generating planar five-membered rings (hydrogen-bridged quasi-rings), in which at least one of the ring atoms is bonded to other non-ring atoms that are not in the ring plane and, thus, capable to form intermolecular interactions, were studied in this work, in order to find the preferred mutual positions of these species in crystals and evaluate strength of intermolecular interactions. We studied parallel interactions of these rings by analysing crystal structures in the Cambridge Structural Database (CSD) and by quantum chemical calculations. The rings can have one hydrogen atom out of the ring plane that can form hydrogen bonds between two parallel rings. Hence, in these systems with parallel rings, two types of hydrogen bonds can be present, one in the ring, and the other one between two parallel rings. The CSD search showed that 27% of the rings in the crystal structures form parallel interactions. The calculations at very accurate CCSD(T)/CBS level revealed strong interactions, in model systems of thiosemicarbazide, semicarbazide and glycolamide dimers the energies are´9.68,´7.12 and 4.25 kcal/mol. The hydrogen bonds between rings, as well as dispersion interactions contribute to the strong interaction energies.

show abstract

Section: Discussionmentioning

confidence: 99%

Very Strong Parallel Interactions Between Two Saturated Acyclic Groups Closed with Intramolecular Hydrogen Bonds Forming Hydrogen-Bridged Rings

2016

View full text Add to dashboard Cite

show abstract

“…The psychotropic and other side effects of clomipramine and thioridazine preclude their ample use in the treatment of trypanosome infections [ 117 ]. However, employing these drugs as molecular scaffolds to construct more active structures by molecular synthesis could be a reasonable strategy in the development of new antitrypanosomal drugs.…”

Section: Discussionmentioning

confidence: 99%

Relevance of Trypanothione Reductase Inhibitors on Trypanosoma cruzi Infection: A Systematic Review, Meta-Analysis, and In Silico Integrated Approach

Mendonça

Coelho

Veloso

et al. 2018

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Due to the rudimentary antioxidant defenses in Trypanosoma cruzi, disruptors of redox balance are promising candidates for new antitrypanosomal drugs. We developed an integrated model based on systematic review, meta-analyses, and molecular modeling to evaluate the effect of trypanothione reductase (TR) inhibitors in T. cruzi infections. Our findings indicated that the TR inhibitors analyzed were effective in reducing parasitemia and mortality due to Trypanosoma cruzi infection in animal models. The most investigated drugs (clomipramine and thioridazine) showed no beneficial effects on the occurrence of infection-related electrocardiographic abnormalities or the affinity and density of cardiac β-adrenergic receptors. The affinity between the tested ligands and the active site of TR was confirmed by molecular docking. However, the molecular affinity score was unable to explain TR inhibition and T. cruzi death in vitro or the antiparasitic potential of these drugs when tested in preclinical models of T. cruzi infection. The divergence of in silico, in vitro, and in vivo findings indicated that the anti-T. cruzi effects of the analyzed drugs were not restricted to TR inhibition. As in vivo studies on TR inhibitors are still scarce and exhibit methodological limitations, mechanistic and highly controlled studies are required to improve the quality of evidence.

show abstract

“…These subsites have been previously used as a template for contact-based analysis in the rational design of potential TR compounds by molecular docking. For example, analogs of clomipramine bearing a tricyclic dibenzosuberyl moiety that showed antitrypanocidal activities in vitro were recognized as competitive inhibitors of TR [24]. Docking studies identified five interaction subsites (γ-GluI, Z, CysI, GlyI and Spm sites) as the binding locations of these tricyclic inhibitors.…”

Section: Identifying the Potential Inhibitors Via Contact-based Analysismentioning

confidence: 99%

“…It is widely known that this computational tool effectively predicts the affinity and binding mode of a given ligand towards a particular macromolecular target [21,22]. Molecular docking has been previously reported as a useful tool in the context of searching potential drugs against T. cruzi using TR, GAPDH, trans-sialidase, polyamine transport and cruzain enzymes as receptors [6,7,9,11,[23][24][25][26][27][28][29][30][31][32][33][34][35]. In the present theoretical study, TR was selected as target taking into account the decisive role of this enzyme in T. cruzi metabolism.…”

Section: Introductionmentioning

confidence: 99%

Identification of novel thiadiazin derivatives as potentially selective inhibitors towards trypanothione reductase from Trypanosoma cruzi by molecular docking using the numerical index poses ratio Pr and the binding mode analysis

et al. 2021

View full text Add to dashboard Cite

Chagas disease is a serious health problem in Central and South America for which effective treatment is not currently available. This illness is caused by the protozoa Trypanosoma cruzi, a species that relies on a thiol-based metabolism to regulate oxidative stress. Trypanothione reductase enzyme plays a central role in the metabolic pathway of the parasite. In this work, a virtual screening of a library of novel thiadiazine derivatives against trypanothione reductase using molecular docking was performed. Four different series of hybrid ligands having in the structure one or two peptoid moieties (series I and II) or the tetrazole ring (series III and IV) were considered. An ad hoc numerical index called poses ratio was introduced to interpret the results of the docking analysis and to establish relevant structure-interaction relationships. In addition, six binding modes were found for the ligands with the highest populated conformational clusters after applying contact-based analysis. The most regular and relevant were binding modes I and II, found mainly for ligands from series I. A subsequent molecular docking on human glutathione reductase enzyme allowed to assess the possible cytotoxicity of the ligands towards human cells. A selective binding profile was found for ligands with interactions in the Hydrophobic cleft, the spermidine and the Z subsites inside the active site of trypanothione reductase. At the end of the study, new thiadiazine-based compounds were identified as plausible candidates to selectively inhibit the parasitic enzyme. Graphic abstract

show abstract

Dibenzosuberyl substituted polyamines and analogs of clomipramine as effective inhibitors of trypanothione reductase; molecular docking, and assessment of trypanocidal activities

Cited by 23 publications

References 125 publications

Very Strong Parallel Interactions Between Two Saturated Acyclic Groups Closed with Intramolecular Hydrogen Bonds Forming Hydrogen-Bridged Rings

Very Strong Parallel Interactions Between Two Saturated Acyclic Groups Closed with Intramolecular Hydrogen Bonds Forming Hydrogen-Bridged Rings

Relevance of Trypanothione Reductase Inhibitors on Trypanosoma cruzi Infection: A Systematic Review, Meta-Analysis, and In Silico Integrated Approach

Identification of novel thiadiazin derivatives as potentially selective inhibitors towards trypanothione reductase from Trypanosoma cruzi by molecular docking using the numerical index poses ratio Pr and the binding mode analysis

Contact Info

Product

Resources

About