Microtubules are polymeric structures formed by the self-assembly of tubulin dimers. The growth and shrinkage of these dynamic arrays have a key role during the cell-proliferation process. This makes tubulin the molecular target of many anticancer drugs currently in use or under clinical trial. Their impressive success is limited by the onset of resistant tumour cells during the treatment, so new resistance-proof molecules need to be developed. Here we use molecular dynamics and free-energy calculations to study the network of interactions that allow microtubule formation. Modelling the protein-protein interface allows us to identify the amino acids responsible for tubulin-tubulin binding and thus to design peptides, which correspond to tubulin subsequences, that interfere with microtubule formation. We show that the application of molecular modelling techniques leads to the identification of peptides that exhibit antitubulin activity both in vitro and in cultured cells.
Experientia 38 (t982), Birkhauser Verlag, CH-4010 Basel/Switzerland storage of the lyophilized peptide in vacuo at +4 ~ for several months produces faint traces of a decomposition product which is detectable by HPLC. 1 S.I. Said and V. Mutt, Science 169, 1217 (i970).
A number of N2-alkyl and N2-acyl derivatives of guanosine 5'-phosphate (GMP) have been synthesized and tested for their synergistic effect with monosodium L-glutamate (MSG), the prototypical substance imparting umami taste to savory-based foods. Capacities to enhance the taste intensity of MSG (gamma values) were estimated through subjective comparisons of MSG/nucleotide mixtures in water with appropriate solutions of MSG alone. Assuming beta = gamma[nucleotide]/gamma[IMP], beta values of the N2-substituted GMPs were found in the range 1.2-5.7. Such values appear to be related to the chain length of the substituent in the 2-position of the purine nucleus and dependent on the replacement of a CH 2 group with an S atom and/or with an alpha-CO group. These findings indicate that the exocyclic NHR group of the guanine moiety is actively implicated in the synergism between GMP derivatives and MSG. Theoretical calculations suggest that an anti conformation is probably assumed by ribonucleotide molecules interacting with umami receptors.
Purine nucleoside phosphorylase (PNP) from Aeromonas hydrophila encoded by the deoD gene has been over-expressed in Escherichia coli, purified, characterized about its substrate specificity and used for the preparative synthesis of some 6-substituted purine-9-ribosides. Substrate specificity towards natural nucleosides showed that this PNP catalyzes the phosphorolysis of both 6-oxo-and 6-aminopurine (deoxy)ribonucleosides. A library of nucleoside analogues was synthesized and then submitted to enzymatic phosphorolysis as well. This assay revealed that 1-, 2-, 6-and 7-modified nucleosides are accepted as substrates, whereas 8-substituted nucleosides are not. A few transglycosylation reactions were carried out using 7-methylguanosine iodide (4) as a d-ribose donor and 6-substituted purines as acceptor. In particular, following this approach, 2-amino-6-chloropurine-9-riboside (2c), 6-methoxypurine-9-riboside (2d) and 2-amino-6-(methylthio)purine-9-riboside (2g) were synthesized in very high yield and purity.
1287Nous tenons ~ exprimer notre gratitude aux Laboratoires Delagrange qui ont mis ~ notre disposition les +chantillons de m~tabolite n6cessaires cette 6tude. Nos remerciements vont 6galement l'Institut de Chimie Pharmaceutique de Lille qui nous a aid+s ~ r6aliser ce travail. la fonction m6thoxy amine les doublets de l'oxyg~ne de part et d'autre de ce plan. I1 en r6sulte deux possibilit6s pour l'6tablissement de la liaison hydrog6ne intramol6culaire, ce qui n'est pas sans r6percussion sur la chaine lat~rale de la mol6cule. Ceci explique sans doute le d6sordre rencontr6 dans cette zone de la molecule de sulpiride.Des 6tudes compl6mentaires sur des compos6s de la m~me famille sont n~cessaires pour confirmer ces rbsultats: c'est dans cette direction que s'orientent actuellement nos travaux. (2)
LAVILLE, C. (1982). Communication priv6e. PREWITT, C. T. (1966). SFLS-5. A Fortran IV Full-Matrix
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.