The 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.
Homology 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.
In 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.
The 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.
T. cruzi is a protozoan pathogen responsible for Chagas disease. Current therapies rely only on a very small number of drugs, most of which are inadequate because of their severe host toxicity or because of their susceptibility to drug-resistance mechanisms. To determine efficient therapeutic alternatives, the identification of new biotargets and detailed knowledge of their structures are essential. Sirtuins from T. cruzi have been recently considered as promising targets for the development of new treatments for Chagas disease. Inhibition of their activity has been shown to significantly interfere with the life cycle of the parasite. T. cruzi possesses genes encoding two sirtuin-like proteins, TcSIR2rp1 and TcSIR2rp3. The structures of these enzymes were theoretically elucidated in this work, which also focused on the impact of their possible conformational states on computational interaction studies. A small library of phytochemicals that are active against the parasite was built and screened against the most meaningful conformations, identifying a restricted number of scaffolds that potentially interact with the modeled proteins. For these hits, a mechanism of action related to interactions with sirtuins was proposed.