Browsing by Author "Maldonado Rojas, Wilson"

Now showing 1 - 6 of 6
  • Thumbnail Image
    Publication
    Computational fishing of new DNA methyltransferase inhibitors from natural products
    (2015-06) Maldonado Rojas, Wilson; Olivero Vebel, Jesús; Marrero Ponce, Yovani
    DNA methyltransferase inhibitors (DNMTis) have become an alternative for cancer therapies. However, only two DNMTis have been approved as anticancer drugs, although with some restrictions. Natural products (NPs) are a promising source of drugs. In order to find NPs with novel chemotypes as DNMTis, 47 compounds with known activity against these enzymes were used to build a LDA-based QSAR model for active/inactive molecules (93% accuracy) based on molecular descriptors. This classifier was employed to identify potential DNMTis on 800 NPs from NatProd Collection. 447 selected compounds were docked on two human DNA methyltransferase (DNMT) structures (PDB codes: 3SWR and 2QRV) using AutoDock Vina and Surflex-Dock, prioritizing according to their score values, contact patterns at 4 ˚A and molecular diversity. Six consensus NPs were identified as virtual hits against DNMTs, including 9,10-dihydro- 12-hydroxygambogic, phloridzin, 2’,4’-dihydroxychalcone 4’-glucoside, daunorubicin, pyrromycin and centaurein. This method is an innovative computational strategy for identifying DNMTis, useful in the identification of potent and selective anticancer drugs.
  • Thumbnail Image
    Publication
    Discovery of antiviral molecules for dengue: in silico search and biological evaluation
    (2014) Cabarcas Montalvo, María; Maldonado Rojas, Wilson; Montes Grajales, Diana Lucía; Bertel Sevilla, Angela; Wagner Döbler, Irene; Sztajer, Helena; Reck, Michael; Flechas Alarcón, María Camila; Ocazionez, Raquel Elvira; Olivero Vebel, Jesús
    Background: Dengue disease is a global disease that has no effective treatment. The dengue virus (DENV) NS2B/NS3 protease complex is a target for designing specific antivirals due to its importance in viral replication and its high degree of conservation. Methods: NS2B/NS3 protease complex structural information was employed to find small molecules that can inhibit the activity of the enzyme complex. This inhibitory activity was probed with in vitro assays using a fluorescent substrateand the complex NS2B/NS3 obtained by recombinant DNA techniques, for testing the activity against dengue virus replication, HepG2 cells infected with dengue virus serotype 2 were used. Results: A total of 210,903 small molecules from PubChem were docked in silico to the NS2B/NS3 structure (PDB: 2FOM) to find molecules that could inhibit this protein complex. Five of the best 500 leading compounds, according to their affinity values (-11.6 and -13.5 kcal/mol), were purchased. The inhibitory protease activity on the recombinant protein and antiviral assays was tested. Conclusions: Chemicals CID54681617, CID54692801 and CID54715399 were strong inhibitors of NS2B/NS3, with IC50 values (μM) and percentages of viral titer reductions of 19.9, 79.9%; 17.5, 69.8%; and 9.1, 73.9 %, respectively. Multivariate methods applied to the molecular descriptors showed two compounds that were structurally different from other DENV inhibitors. General significance: This discovery opens new possibilities for obtaining drug candidates against Dengue virus.
  • Thumbnail Image
    Publication
    Essential oil constituents as ecdysone receptor ligands of pest insects: in silico approach with autodock vina
    (2015) Maldonado Rojas, Wilson; Hernandez Lambraño, Ricardo; Olivero Vebel, Jesús
    The search for alternatives to the insect pest control has become a major global worry. These factor added to climate change may affect severely the agricultural production. Synthetic chemicals have been used as a system of control of these types of insects, although their application has raised various concerns including environment and human health damage. Nevertheless, the use of natural compounds, primarily those derived from plants like essential oils have been proposed as alternative for this purpose. Some authors have proposed different protein targets, among them chitin synthase, nicotinic acetylcholine receptor (nAChR), gamma-amino butyric acid (GABA) receptor and ecdysone receptor (EcR). However, the biochemical mechanisms responsible of their insecticide action are still lacking information. In this work, 47 constituents of essential oils were evaluated in silico in order to identify potential agonist of the ecdysone receptor to four pest insect species (Bemisia tabaci; 1Z5X, Tribolium castaneum, 2NXX, Heliothis virescens; 2R40, Helicoverpa armigera; 3IXP) using molecular docking protocols with AutoDock Vina 1.1 program. The results showed that essential oils constituents such as Camphorene, Kaur-16-ene, Pimara-7,15-dien-3-one, Pimara-7,15-dien-3-ol, Virifidol produced promising theoretical affinity values (between -8.2 to -8.8 kcal/mol) taking as reference the mean affinity value (-8.2 kcal/mol) obtained for eleven EcR LBD agonists with biological activity reported in the literature. AutoDock Vina affinities scores for several EcR LDB active compounds on the four different structures evaluated, found that only for H. virescen (PDB: 2R40) showed a significant linear correlation (r = 0.688, p-value <0.028) for theoretical affinity values and biological activity data, supporting the computational reliability of the predictions made by our docking simulations. Theoretical approaches suggest that these constituents of essential oils may be applied as possible natural insecticide agents and will provide a platform for structure-based design of stronger and selective insecticides with a lower risk to the environment and humans.
  • Thumbnail Image
    Publication
    In silico search of protein targets for fullerenes
    (2014) Acosta, Javier; Maldonado Rojas, Wilson; Olivero Vebel, Jesús
    Fullerenes are a group of nanomaterials with an extensive range of applications, but little is known about the effects on biochemical processes linked to these nanoparticles. For these reason, the innovative techniques of virtual screening and molecular docking were applied to search for target proteins and discuss the fullerene exposure effects on these proteins functions and behavior. PatchDock software was employed to calculate the theoretical affinity through the atomic contact energy (ACE) of C60 fullerene, C70 fullerene and their respective derivatives of propanedioic acid and 1,2 diphenylethanol docked to 118 proteins structures previously selected from the potential drug target database (PDTD). Glucocorticoid receptor and estrogen receptor alpha (PDB code: 1NHZ and 3ERT respectively) showed the most remarkable affinity value when docked with all optimized fullerene structures specially C70-Diphenyleathanol which achieved -50.43 kcal/mol and - 40.22 kcal/mol with each protein, values much higher than those achieved by the 1NHZ well known inhibitor antiprogestin mifepristone (RU486) (-15.75 kcal/mol) and 3ERT inhibitor 4-Hidroxitamoxifen (-13.76 kcal/mol). Whereas, these proteins have been related with hormonal function, eukaryotic gene expression and mental illnesses such as psychotic depression, bipolar disorder and schizophrenia a precedent for the possible treatment of these diseases using fullerene derivatives for protein inhibition is here establish. PatchDock ACE results for several fullerenes derivatives significantly correlated with reported median inhibitory concentrations (R2 = 0.6135, P<0.0125), supporting the computational reliability of the prediction made by our docking simulations.
  • Thumbnail Image
    Publication
    Novel NS2B/NS3-protease dengue virus inhibitors
    (2014) Cabarcas Montalvo, María; Olivero Vebel, Jesús; Montes Grajales, Diana Lucía; Maldonado Rojas, Wilson; Bertel Sevilla, Angela; Wagner Döbler, Irene; Sztajer, Helena; Reck, Michael; Flechas Alarcón, María Camila; Ocazionez, Raquel Elvira
    Dengue disease, caused by the virus of the same name, is expanding globally with an annual estimate of 390 million people infected. However, available antivirals have been ineffective. Therefore, the search of small-molecule therapeutic candidates is a recurrent practice. The dengue virus (DENV) NS2B/NS3 protease complex is a recognized target for the design of specific antivirals, due to its importance in the replication and high degree of sequence conservation. The aim of this research was to find molecules capable of inhibiting this protein complex. A total of 210,903 molecules, from the PubChem database, were docked in silico to the NS2B/NS3 crystallographic structure (PDB: 2FOM). The recombinant protease was expressed in E. coli and purified by affinity chromatography. Five of the best 500 leading compounds, according to the virtual screening affinity values (-11.6 and -13.5 kcal/mol), were purchased. The inhibitory activity of these molecules by the protease was evaluated in vitro, using the action of the recombinant enzyme on the Boc-Gly-Arg-Arg-AMC substrate (IC50), and antiviral assays for the detection of NS1 viral titles in infected human hepatocytes. Compounds CID54681617, CID54692801, and CID54715399 showed to be strong inhibitors of NS2B/NS3, with IC50 values (μM) and percentages of NS1 viral title reductions corresponding to 19.9, 79.9%; 17.5, 69.8%; 9.1, 73.9 %, respectively. Multivariate methods on molecular descriptors showed that two of these compounds are structurally different from DENV inhibitors reported by other authors. This discovery opens new possibilities to obtain drug candidates against Dengue.
  • Thumbnail Image
    Publication
    Searching of new natural DNA methyltransferase inhibitors using computational approach
    (2015) Maldonado Rojas, Wilson; Marrero Ponce, Yovani; Olivero Vebel, Jesús
    The searching of DNA methyltransferases inhibitors (DNMTs), therapeutic targets in cancer, is currently a scientific priority. However, only two DNMTs inhibitors have been approved as anticancer drugs, although with some restrictions. Natural products (NPs) are a promising source of drugs due to their wide molecular diversity and low toxicity. In order to find NPs with novel chemotypes for inhibitors of DNMTs, in this study an in silico searching was performed using a combination of QSAR and protein-ligand docking. A set of 47 compounds with known activity against these enzymes was used to construct a discriminating model of active/inactive molecules (93% accuracy), based on physicochemical descriptors generated by the DRAGON program. This classifier was used to identify potential DNMTs inhibitors on 800 NPs from the NatProd Collection (www.msdiscovery.com/natprod.html). 447 selected compounds were docked on two human DNMTs structures (DNMT1:3SWR and DNMT3A:2QRV) using AutoDock Vina and Surflex-Dock programs, with subsequent prioritization according to their score values, contact patterns at 4 Å and molecular diversity from clustering (k-means). Six NPs with novel chemotypes were identified as virtual hits against DNMTs, including 9,10-dihydro 12-hydroxygambogic, phloridzin, 2',4'-dihydroxychalcone 4'-glucoside, daunorubicin, pyrromycin and centaurein. The methodology proposed in this study is an innovative computational tool for identifying DNMT inhibitors, useful in the design of more potent and selective anticancer drugs.