Computational Studies on Sirtuins from Trypanosoma cruzi: Structures, Conformations and Interactions with Phytochemicals

Abstract

BackgroundThe silent-information regulator 2 proteins, otherwise called sirtuins, are currently considered as emerging anti-parasitic targets. Nicotinamide, a pan-sirtuin inhibitor, is known to cause kinetoplast alterations and the arrested growth of T. cruzi, the protozoan responsible for Chagas disease. These observations suggested that sirtuins from this parasite (TcSir2rp1 and TcSir2rp3) could play an important role in the regulation of the parasitic cell cycle. Thus, their inhibition could be exploited for the development of novel anti-trypanosomal compounds.MethodsHomology modeling was used to determine the three-dimensional features of the sirtuin TcSir2rp1 from T. cruzi. The apo-form of human SIRT2 and the same structure solved in complex with its co-substrate NAD+ allowed the modeling of TcSir2rp1 in the open and closed conformational states. Molecular docking studies were then carried out. A library composed of fifty natural and diverse compounds that are known to be active against this parasite, was established based on the literature and virtually screened against TcSir2rp1 and TcSir2rp3, which was previously modeled by our group.ResultsIn this study, two conformational states of TcSir2rp1 were described for the first time. The molecular docking results of compounds capable of binding sirtuins proved to be meaningful when the closed conformation of the protein was taken into account for calculations. This specific conformation was then used for the virtual screening of antritrypanosomal phytochemicals against TcSir2rp1 and TcSir2rp3. The calculations identified a limited number of scaffolds extracted from Vismia orientalis, Cussonia zimmermannii, Amomum aculeatum and Anacardium occidentale that potentially interact with both proteins.ConclusionsThe study provided reliable models for future structure-based drug design projects concerning sirtuins from T. cruzi. Molecular docking studies highlighted not only the advantages of performing in silico interaction studies on their closed conformations but they also suggested the potential mechanism of action of four phytochemicals known for their anti-trypanosomal activity in vitro.

Characterization of Trypanosoma cruzi Sirtuins as Possible Drug Targets for Chagas Disease

“…This pronounced effect might be due to the low expression levels of endogenous protein in metacyclic trypomastigote and amastigote forms of the parasite in which the overexpression of a mutated version of the protein acted as a dominant negative in these forms, perhaps by competing with protein substrates and cofactors, such as NAD ϩ . The key role of sirtuins in the regulation of vital cellular processes in T. cruzi supports their use as targets for drug development, as proposed recently (23,(59)(60)(61). Here, we used salermide, a specific sirtuin inhibitor that had been tested for treatment of some kinds of cancers in vitro and in vivo, with high efficacy (39).…”

Nicotinamide mononucleotide adenylyltransferase of Trypanosoma cruzi (TcNMNAT): a cytosol protein target for serine kinases

“…In the cytosol, the synthesis of the calcium-mobilising molecules, such as NAADP, occurs along with the NAD+-dependent deacetylation of proteins by sirtuins such as TcSir2rpl, an enzyme involved in the proliferation of the replication forms of the parasite and in life-cycle differentiation, among other things (Sacconnay et al 2014, Ritagliati et al 2015). These processes require a constant supply of NAD+, explaining the presence of this enzyme in the cytosol.…”

Identification of Bichalcones as Sirtuin Inhibitors by Virtual Screening and <em>in Vitro </em>Testing

“…10 low energy conformers were generated for each molecule and MMFF94 force field [56] implemented in MOE [54] 15 was used for minimization. Pan-Assay Interference (PAIN) filters were applied using Schrodinger's Canvas tool [57] and CbLigand web server [58].…”

“…Recently, virtual screening for the identification of sirtuin inhibitors and modulators has received great interest [12][13][14][15][16][17][18][19][20]. Sirtuins are nicotinamide adenine dinucleotide (NAD + )-dependent class III histone deacetylases that have been linked to the pathogenesis of numerous diseases such as HIV, metabolic disorders, neurodegeneration (including Alzheimer's disease and Parkinson's disease) and cancer [21][22][23][24][25][26][27][28].…”