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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.

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VIRTUAL SCREENING OF SUBSTANCES WITH POTENTIAL ANTIVIRAL ACTIVITY AGAINST THREE FLAVIVIRUSES: dengue virus, yellow fever virus and Zika virus

VIRTUAL SCREENING OF SUBSTANCES WITH POTENTIAL ANTIVIRAL ACTIVITY AGAINST THREE FLAVIVIRUSES: dengue virus, yellow fever virus and Zika virus

Mateus Serafim, Thales Kronenberger, Rafael Rocha, Rafaela Ferreira, Vinícius Maltarollo, Bruno Mota and Erna Kroon

Approximately three billion people live in regions at risk of infections by flaviviruses. Dengue virus (DENV), Zika virus (ZIKV) and Yellow fever virus (YFV) presents outbreaks and severe complications. Currently, there are no antivirals available to treat these diseases. We screened and evaluated the potential antiviral activity of small molecules against these viruses, targeting the viral protease NS2B-NS3 (NS3PRO). We used a combination of HQSAR models and structural molecular modelling, based on structures of peptidomimetic DENV-3 NS3PRO inhibitors and molecular docking studies to screen for new compounds. Binding sites of DENV-3 and ZIKV NS3PRO were assessed to build a pharmacophoric model for virtual screening. Hits were selected after molecular dynamics simulations, with predictions of toxicity and biological activity. Biological activities were evaluated by the MTT assay. Antiviral activity was evaluated by plaque reduction, pre-treatment and virucide activity assays. Enzymatic inhibition assays against ZIKV NS3PRO were carried out. An optimal HQSAR model (q2 = 0.67; r2 = 0.87) was selected. A virtual screening of ~7,600,000 compounds was conducted (pharmacophore, docking and molecular dynamics), identifying eight potential inhibitors to the NS3PRO, with favorable biological activity (5/8) and toxicity (8/8) predictions. Five were active against ZIKV, YFV, DENV-2 or DENV-3 (EC50 from 4.21 ± 0.14 to 37.51 ± 0.8 µM, with selective indexes from 1.42 to 3.74), with one being active against all viruses. In plaque reduction assays, two substances reduced about 1.0 to 1.5 log10 of the viral titer of ZIKV, YFV and DENV-2. One also reduced about 1.0 log10 of YFV titer in pre-treatment assays. We have identified five compounds with antiviral activity, with one showing a potential panflavivirus activity. Preliminary ZIKV NS3PRO inhibition assays showed three active compounds with IC50 values between 28 and 69 µM.