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De Novo Design (de + novo_design)
Selected AbstractsSynthesis of Components for the Generation of Constitutional Dynamic Analogues of Nucleic AcidsHELVETICA CHIMICA ACTA, Issue 1 2008David Abstract The introduction of dynamic covalent polymers, in which the monomer units are linked by reversible covalent bonds and can undergo component exchange, opens up new possibilities for the generation of functional materials. Extending this approach to the generation of dynamic biopolymers in aqueous media, which are able to adapt constitution (sequence, length) to external factors (e.g., environment, medium, template), would provide an alternative approach to the de novo design of functional dynamic bio-macromolecules. As a first step towards this goal, various mono- and bifunctionalised (hetero- and homotopic) nucleic acid-derived building blocks of type I,X have been synthesised for the generation of dynamic main-chain and side-chain reversible nucleic acid analogues. Hydrazide- and/or acetal (protected carbonyl)-functionalised components were selected, which differ in terms of flexibility, length, net formal charge, and hydrazide/acetal substituents, in order to explore how such factors may affect the properties (structure, solubility, molecular recognition features) of the polymer products that may be generated by polycondensation. [source] Second-Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis, Biological Activity, and X-Ray Crystal-Structure AnalysisHELVETICA CHIMICA ACTA, Issue 4 2005Stefan Sahli A new class of nonpeptidic inhibitors of the ZnII -dependent metalloprotease neprilysin with IC50 values in the nanomolar activity range (0.034,0.30,,M) were developed based on structure-based de novo design (Figs.,1 and 2). The inhibitors feature benzimidazole and imidazo[4,5- c]pyridine moieties as central scaffolds to undergo H-bonding to Asn542 and Arg717 and to engage in favorable , - , stacking interactions with the imidazole ring of His711. The platform is decorated with a thiol vector to coordinate to the ZnII ion and an aryl residue to occupy the hydrophobic S1, pocket, but lack a substituent for binding in the S2, pocket, which remains closed by the side chains of Phe106 and Arg110 when not occupied. The enantioselective syntheses of the active compounds (+)- 1, (+)- 2, (+)- 25, and (+)- 26 were accomplished using Evans auxiliaries (Schemes,2, 4, and 5). The inhibitors (+)- 2 and (+)- 26 with an imidazo[4,5- c]pyridine core are ca. 8 times more active than those with a benzimidazole core ((+)- 1 and (+)- 25) (Table,1). The predicted binding mode was established by X-ray analysis of the complex of neprilysin with (+)- 2 at 2.25-Å resolution (Fig.,4 and Table,2). The ligand coordinates with its sulfanyl residue to the ZnII ion, and the benzyl residue occupies the S1, pocket. The 1H -imidazole moiety of the central scaffold forms the required H-bonds to the side chains of Asn542 and Arg717. The heterobicyclic platform additionally undergoes ,-, stacking with the side chain of His711 as well as edge-to-face-type interactions with the side chain of Trp693. According to the X-ray analysis, the substantial advantage in biological activity of the imidazo-pyridine inhibitors over the benzimidazole ligands arises from favorable interactions of the pyridine N-atom in the former with the side chain of Arg102. Unexpectedly, replacement of the phenyl group pointing into the deep S1, pocket by a biphenyl group does not enhance the binding affinity for this class of inhibitors. [source] Metallo-Supramolecular Polymers Based on Functionalized Bis-terpyridines as Novel Electrochromic Materials,ADVANCED MATERIALS, Issue 22 2007S. Han Self-assembly of various metallo-supramolecular coordination polyelectrolytes (MEPEs) based on pyridine ring functionalized ditopic bis-terpyridines, as well as the electrochromic property is presented. MEPEs derived from electron-donating OMe functionalized ligands exhibit rapid switching rates, good reversibility, high stability, and an optical memory. The first structure-property relationships are proposed, which are needed for the de novo design and fabrication of new materials. [source] Antitumour activity and specificity as a function of substitutions in the lipophilic sector of helical lactoferrin-derived peptideJOURNAL OF PEPTIDE SCIENCE, Issue 5 2003Nannan Yang Abstract A peptide L5 (PAWRKAFRWAWRMLKKAA), derived from the N -terminal ,-helical region of bovine lactoferrin (LFB 14,31), that is highly active against several tumour cell lines was reported earlier. In this study, a number of L5 analogues were designed in order to investigate how subsequent replacements of the aromatic amino acids in L5 with three amino acids representing different structural parameters influenced antitumour activity and tumour cell specificity relative to normal human cells. The Trp residues were substituted by Lys, Ile or Ala, while the Phe residue was substituted with Ala. The resulting peptides were investigated for their activity against prokaryotic cells, four tumour cell lines, human lung fibroblasts and human erythrocytes. Most of the peptides were highly active against both E. coli and S. aureus. The peptides were more active against the tumour cell lines than against normal eukaryotic cells but the activity against normal fibroblasts varied more among the peptides than did their antitumour activities. The results revealed that aromatic residues located opposite the cationic sector in L5 were more critical for antitumour activity than were aromatic residues located adjacent to the cationic sector. The biological responses for the peptides against tumour cell lines, fibroblasts, S. aureus (but not E. coli), were highly correlated with the amino acid descriptors used in our QSAR model. The result obtained from the QSAR study identified specific structural features that were important for lytic activity and membrane specificity. Certain structural properties in positions 3, 9 and 11 were shown to be important for antitumour activity, while additional structural properties in position 7 were found to be important with respect to tumour cell specificity. This information may offer a possibility for de novo design of an antitumour peptide with an improved therapeutic index. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd. [source] Perfluorocarbons: Life sciences and biomedical uses Dedicated to the memory of Professor Guy Ourisson, a true RENAISSANCE man.JOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 7 2007Marie Pierre Krafft Abstract Perfluorocarbons are primarily characterized by outstanding chemical and biological inertness, and intense hydrophobic and lipophobic effects. The latter effects provide a powerful noncovalent, labile binding interaction that can promote selective self- assembly. Perfluoro compounds do not mimic nature, yet they can offer abiotic building blocks for the de novo design of functional biopolymers and alternative solutions to physiologically vital issues. They offer new tags useful for molecular recognition, selective sorting, and templated binding (e.g., selective peptide and nucleic acid pairing). They also stabilize membranes and provide micro- and nanocompartmented fluorous environments. Perfluorocarbons provide inert, apolar carrier fluids for lab-on-a-chip experiments and assays using microfluidic technologies. Low water solubility, combined with high vapor pressure, allows stabilization of injectable microbubbles that serve as contrast agents for diagnostic ultrasound imaging. High gas solubilities are the basis for an abiotic means for intravascular oxygen delivery. Other biomedical applications of fluorocarbons include lung surfactant replacement and ophthalmologic aids. Diverse colloids with fluorocarbon phases and/or shells are being investigated for molecular imaging using ultrasound or magnetic resonance, and for targeted drug delivery. Highly fluorinated polymers provide a range of inert materials (e.g., fluorosilicons, expanded polytetrafluoroethylene) for contact lenses, reconstructive surgery (e.g., vascular grafts), and other devices. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 1185,1198, 2007. [source] Design of a minimal protein oligomerization domain by a structural approachPROTEIN SCIENCE, Issue 12 2000Peter Burkhard Abstract Because of the simplicity and regularity of the ,-helical coiled coil relative to other structural motifs, it can be conveniently used to clarify the molecular interactions responsible for protein folding and stability. Here we describe the de novo design and characterization of a two heptad-repeat peptide stabilized by a complex network of inter- and intrahelical salt bridges. Circular dichroism spectroscopy and analytical ultracentrifugation show that this peptide is highly ,-helical and 100% dimeric under physiological buffer conditions. Interestingly, the peptide was shown to switch its oligomerization state from a dimer to a trimer upon increasing ionic strength. The correctness of the rational design principles used here is supported by details of the atomic structure of the peptide deduced from X-ray crystallography. The structure of the peptide shows that it is not a molten globule but assumes a unique, native-like conformation. This de novo peptide thus represents an attractive model system for the design of a molecular recognition system. [source] Computational Design of Four-Helix Bundle Proteins That Bind Nonbiological CofactorsBIOTECHNOLOGY PROGRESS, Issue 1 2008Andreas Lehmann Recent work is discussed concerning the computational design of four-helix bundle proteins that form complexes with nonbiological cofactors. Given that often there are no suitable natural proteins to provide starting points in the creation of such nonbiological systems, computational design is well suited for the design and study of new protein-cofactor complexes. Recent design efforts are presented in the context of prior work on the de novo design and engineering of porphyrin-binding four-helix bundle proteins and current developments in nonlinear optical materials. Such protein-nonbiological cofactor complexes stand to enable new applications in protein science and materials research. [source] Structure-Based Design, Synthesis, and in vitro Evaluation of Nonpeptidic Neprilysin InhibitorsCHEMBIOCHEM, Issue 7 2004Stefan Sahli Dipl.-Chem. Using X-ray structure-based de novo design, a new class of inhibitors of the zinc-dependent endopeptidase Neprilysin has been developed that feature binding affinities (IC50 values) in the upper nanomolar range. The imidazole moieties of the central benzimidazole or imidazo[4,5- c]pyridine (see picture) scaffolds act as efficient peptide-bond isosters. [source] Hydrogen-Bonding Cooperativity: Using an Intramolecular Hydrogen Bond To Design a Carbohydrate Derivative with a Cooperative Hydrogen-Bond Donor CentreCHEMISTRY - A EUROPEAN JOURNAL, Issue 17 2004Virginie Vicente Dr. Abstract Neighbouring groups can be strategically located to polarise HO,,,OH intramolecular hydrogen bonds in an intended direction. A group with a unique hydrogen-bond donor or acceptor character, located at hydrogen-bonding distance to a particular OH group, has been used to initiate the hydrogen-bond network and to polarise a HO,,,OH hydrogen bond in a predicted direction. This enhanced the donor character of a particular OH group and made it a cooperative hydrogen-bond centre. We have proved that a five-membered-ring intramolecular hydrogen bond established between an amide NH group and a hydroxy group (1,2-e,a), which is additionally located in a 1,3 -cis- diaxial relationship to a second hydroxy group, can be used to select a unique direction on the six-membered-ring intramolecular hydrogen bond between the two axial OH groups, so that one of them behaves as an efficient cooperative donor. Talose derivative 3 was designed and synthesised to prove this hydrogen-bonding network by NMR spectroscopy, and the mannopyranoside derivatives 1 and 2 were used as models to demonstrate the presence in solution of the 1,2-(e,a)/five-membered-ring intramolecular hydrogen bond. Once a well-defined hydrogen-bond is formed between the OH and the amido groups of a pyranose ring, these hydrogen-bonding groups no longer act as independent hydrogen-bonding centres, but as hydrogen-bonding arrays. This introduces a new perspective on the properties of carbohydrate OH groups and it is important for the de novo design of molecular recognition processes, at least in nonpolar media. Carbohydrates 1,3 have shown to be efficient phosphate binders in nonpolar solvents owing to the presence of cooperative hydroxy centres in the molecule. [source] | |||||||||||||