Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery

Dimethylmyricacene: An In Vitro and In Silico Study of a Semisynthetic Non-Camptothecin Derivative Compound, Targeting Human DNA Topoisomerase 1B

Human topoisomerase 1B regulates the topological state of supercoiled DNA enabling all fundamental cell processes. This enzyme, which is the unique molecular target of the natural anticancer compound camptothecin, acts by nicking one DNA strand and forming a transient protein–DNA covalent complex. The interaction of human topoisomerase 1B and dimethylmyricacene, a compound prepared semisynthetically from myricanol extracted from Myrica cerifera root bark, was investigated using enzymatic activity assays and molecular docking procedures. Dimethylmyricacene was shown to inhibit both the cleavage and the religation steps of the enzymatic reaction, and cell viability of A-253, FaDu, MCF-7, HeLa and HCT-116 tumor cell lines

Leishmanicidal compounds of Nectria pseudotrichia, an endophytic fungus isolated from the plant Caesalpinia echinata (Brazilwood)

Fundação Oswaldo Cruz. Instituto René Rachou. Laboratório de Química de Produtos Naturais Bioativos. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Instituto René Rachou. Laboratório de Genômica Funcional e Proteômica de Leishmania spp. e Trypanosoma cruzi. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Instituto René Rachou. Laboratório de Química de Produtos Naturais Bioativos. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Departamento de Fisiologia e Biofísica. Belo Horizonte, MG, BrasilUniversidade Estadual do Sudoeste da Bahia. Departamento de Química. Jequié, BA, BrasilFundação Oswaldo Cruz. Instituto René Rachou. Laboratório de Química de Produtos Naturais Bioativos. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Instituto René Rachou. Laboratório de Química de Produtos Naturais Bioativos. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Departamento de Fisiologia e Biofísica. Belo Horizonte, MG, BrasilUniversidade Federal dos Vales do Jequitinhonha e Mucuri. Departamento de Ciências Biológicas e da Saúde. Diamantina, MG, BrasilFundação Oswaldo Cruz. Instituto René Rachou. Laboratório de Química de Produtos Naturais Bioativos. Belo Horizonte, MG, BrasilBACKGROUND: In a screen of extracts from plants and fungi to detect antileishmanial activity, we found that the ethyl acetate extract of the fungus Nectria pseudotrichia, isolated from the tree Caesalpinia echinata (Brazilwood), is a promising source of bioactive compounds. OBJECTIVES: The aims of this study were to isolate and determine the chemical structures of the compounds responsible for the antileishmanial activity of the organic extract from N. pseudotrichia. METHODS: Compounds were isolated by chromatographic fractionation using semi-preparative high-performance liquid chromatography, and their chemical structures were determined by analytical and spectral data and by comparison with published data. The antileishmanial activity of the isolated compounds was evaluated in intracellular amastigote forms of Leishmania (Viannia) braziliensis expressing firefly luciferase as reporter gene, and cytotoxicity was determined in Vero and THP-1 mammalian cell lines by MTT assay. FINDINGS: Fractionation of the extract yielded seven compounds: 10-acetyl trichoderonic acid A (1), 6′-acetoxy-piliformic acid (2), 5′,6′-dehydropiliformic acid (3), piliformic acid (4), hydroheptelidic acid (5), xylaric acid D (6), and cytochalasin D (7). Compounds 1, 2 and 3 are reported here for the first time. Compounds 1, 2, and 5 were more active, with IC50 values of 21.4, 28.3, and 24.8 µM, respectively, and showed low toxicity to Vero and THP-1 cells. MAIN CONCLUSIONS: N. pseudotrichia produces secondary metabolites that are more toxic to intracellular amastigote forms of L. (V.) braziliensis than to mammalian cells

Novel Alkaloids of the Aaptamine Class from an Indonesian Marine Sponge of the Genus Xestospongia

International audienceFour novel alkaloids of the aaptamine class have been isolated in addition to the known aaptamine, isoaaptamine, demethyl(oxy)aaptamine and its dimethylketal from an unidentified species of Indonesian marine sponge of the genus Xestospongia. Their structures were elucidated on the basis of detailed 1D and 2D NMR spectroscopic data. Their antimicrobial activity was tested towards Gram (+) (S. aureus), Gram (−) (E. coli, V. anguillarum) bacterial strains, a fungus (C. tropicalis); their cytotoxic activity was evaluated against KB cells

Series de Chebyshev formelles

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : 17660, issue : a.1996 n.960-M / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Image processing throught reaction combined with nonlinear diffusion

Available at INIST (FR), Document Supply Service, under shelf-number : 22495, issue : a.1992 n.78 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueSIGLEFRFranc