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The HGPRT AND XPRT ENZYMES FROM Leishmania donovani: MOLECULAR MODELING AND STUDY OF DUAL INHIBITORS.

The HGPRT AND XPRT ENZYMES FROM Leishmania donovani: MOLECULAR MODELING AND STUDY OF DUAL INHIBITORS.

Lucas Sousa Palmeira and Bruno Silva Andrade

Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT) and Xanthine Phosphoribosyltransferase (XPRT) are classified in the type I PRTases family, which are responsible for purine recycling in the organism to which they belong. Protozoans of the order Kinetoplastidae such as Leishmania spp. cannot make de novo purine synthesis, and they have only the recovery route. The aim of this work was to perform molecular homology modeling of both HGPRT and XPRT targets, as well as to perform a virtual screening in order to search dual inhibitor for both enzymes. The 3D structures of HGPRT and XPRT from Leishmania donovani (Laveran and Mesnil, 1903) were constructed by the Swiss-Model Workspace, considering the best available crystallographic templates for both targets. The ROCS program (Openeye Scientific Software) was used to develop five pharmacophore structures, which were based on five active compounds for type I PRTases. Then, we submitted the pharmacophore structures to a ROCS searching a database of 57,000 compounds from natural sources extracted from ZINC DATABASE, in which a total number of 1,825 compounds (hits) for the five pharmacophores were returned. In a second step, we performed a receptor-based virtual screening (RVBS) using AutoDock Vina for molecular docking calculations. The 50 best compounds for both enzymes obtained affinity energies between -8.4 and -10.9 Kcal/mol, of which ZINC4096947, ZINC519733, ZINC485610, ZINC2150030 and ZINC58116 presented best values for both enzymes, as well as Lipinski’s rule of five characteristics. Molecular dynamics calculations revealed that the compound ZINC2150030 remained within the active site of both enzymes after 50 ns. Additionally, this inhibitor candidate can be tested in vitro and in vivo as a new treatment option for leishmaniasis.