Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase.

Department of Biochemistry, Duke University Medical Center, Box 3711, Durham, NC 27710, USA.
Chemistry & biology (Impact Factor: 6.59). 03/2009; 16(2):181-92. DOI: 10.1016/j.chembiol.2009.01.014
Source: PubMed

ABSTRACT Protein farnesyltransferase (FTase) catalyzes an essential posttranslational lipid modification of more than 60 proteins involved in intracellular signal transduction networks. FTase inhibitors have emerged as a significant target for development of anticancer therapeutics and, more recently, for the treatment of parasitic diseases caused by protozoan pathogens, including malaria (Plasmodium falciparum). We present the X-ray crystallographic structures of complexes of mammalian FTase with five inhibitors based on an ethylenediamine scaffold, two of which exhibit over 1000-fold selective inhibition of P. falciparum FTase. These structures reveal the dominant determinants in both the inhibitor and enzyme that control binding and selectivity. Comparison to a homology model constructed for the P. falciparum FTase suggests opportunities for further improving selectivity of a new generation of antimalarial inhibitors.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Naturally occurring anticancer compounds represent about half of the chemotherapeutic drugs which have been put in the market against cancer till date. Computer-based or in silico virtual screening methods are often used in lead/hit discovery protocols. In this study, the “drug-likeness” of ~400 compounds from African medicinal plants, which have shown in vitro and/or in vivo anticancer, cytotoxic and antiproliferative activities has been explored. To verify potential binding to anticancer drug targets, the interactions between the compounds and fourteen selected targets have been analyzed by in silico modelling. Docking and binding affinity calculations were carried out, in comparison with known anticancer agents comprising ~1,500 published naturally occurring plant-based compounds from around the world. The results reveal that African medicinal plants could represent a good starting point for the discovery of anticancer drugs. The small dataset generated (named AfroCancer) has been made available for research groups working on virtual screening.
    Journal of Chemical Information and Modeling 08/2014; 54(9):2433–2450. DOI:10.1021/ci5003697 · 4.07 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Two series of farnesyltransferase (FTase) inhibi-tors were grouped and their antimalarial activi-ties modeled by means of multivariate image analysis applied to quantitative structure-activ-ity relationship (MIA-QSAR). A reliable model was achieved, with r 2 for calibration, external prediction and leave-one-out cross-validation of 0.96, 0.87 and 0.83, respectively. Therefore, bio-logical activities of congeners can be estimated using the QSAR model. The bioactivities of new compounds based on the miscellany of sub-structures of the two classes of FTase inhibitors were predicted using the MIA-QSAR model and the most promising ones were submitted to ADME (absorption, distribution, metabolism and excretion) and docking evaluation. Despite the smaller interaction energy of the two most pro-mising, predicted compounds in comparison to the two most active compounds of the data set, one of the proposed structures did not violate any Lipinski's rule of five. Therefore, it is either a potential drug or may drive synthesis of similar, improved compounds.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Protein farnesytransferase (PFTase) catalyzes the farnesylation of proteins with a carboxy-terminal tetrapeptide sequence denoted as a Ca1a2X box. To explore the specificity of this enzyme, an important therapeutic target, solid phase peptide synthesis in concert with a peptide inversion strategy were used to prepare two libraries, each containing 380 peptides. The libraries were screened using an alkyne-containing isoprenoid analogue followed by click chemistry with biotin azide and subsequent visualization with streptavidin-AP. Screening of the CVa2X and CCa2X libraries with R. norvegicus PFTase revealed reaction by many known recognition sequences as well as numerous unknown ones. Some of the latter occur in the genomes of bacteria and viruses and may be important for pathogenesis, suggesting new targets for therapeutic intervention. Screening of the CVa2X library with alkyne-functionalized isoprenoid substrates showed that those prepared from C10 or C15 precursors gave similar results while the analogue synthesized from a C5 unit gave a different pattern of reactivity. Finally the substrate specificities of PFTases from three organisms (R. norvegicus, S. cerevisiae and C. albicans) were compared using CVa2X libraries. R. norvegicus PFTase was found to share more peptide substrates with S. cerevisiae PFTase than with C. albicans PFTase. In general, this method is a highly efficient strategy for rapidly probing the specificity of this important enzyme.
    ACS Chemical Biology 05/2014; 9(8). DOI:10.1021/cb5002312 · 5.36 Impact Factor

Full-text (2 Sources)

Available from
Jun 6, 2014