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Additional Interactions (additional + interaction)
Selected AbstractsInteractions of cyclosporines with lipid membranes as studied by solid-state nuclear magnetic resonance spectroscopy and high-sensitivity titration calorimetryJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2002Uwe Schote Abstract Cyclosporin A (CyA) interacts with lipid membranes. Binding reaction and membrane location of CyA and analogs were examined with 2H-NMR, high-sensitivity isothermal titration calorimetry (ITC), and CD spectroscopy. Effects of CyA and charged analogs on the phosphocholine head group and on the membrane interior were investigated using selectively deuterated phospholipids. Incorporation of cyclosporin generated small disordering of the lipid acyl chains. Binding of CyA and neutral and positively charged analogs to lipid membranes showed endothermic heats of reaction between +,5.9 and +,11.3 kcal/mol, whereas enthalpy of binding was close to zero for the negatively charged derivative. Binding constants of cyclosporines to liposomal membranes were in the range of KP,=,1650,5560 M,,1 depending on the cholesterol content. 2H-NMR provides evidence that CyA is essentially located in the interior of the bilayer membrane. For the charged analogs an additional interaction occurs at the head group level, placing the polar groups of these CyA analogs in the vicinity of the phosphocholine dipoles. The association of CyA and its analogs is accompanied by a positive enthalpy change, which is overcompensated by positive entropy changes. Binding of CyA to lipid membranes thus follows the classical hydrophobic effect, which is in contrast to many other peptide-lipid binding reactions. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91: 856,867, 2002 [source] Bonding and Bending in Zirconium(IV) and Hafnium(IV) HydrazidesCHEMISTRY - A EUROPEAN JOURNAL, Issue 27 2008Heike Herrmann Dr. Abstract Reaction of the dichloro complexes [M(N2TBSNpy)Cl2] (M=Zr: 1, Hf: 2; TBS: tBuMe2Si; py: pyridine) with one molar equivalent of LiNHNPh2 gave mixtures of the two diastereomeric chlorohydrazido(1,) complexes [M(N2TBSNpy)(NHNPh2)Cl] (M=Zr: 3,a,b, Hf: 4,a,b) in which the diphenylhydrazido(1,) ligand adopts a bent ,1 coordination. This mixture of isomers could be cleanly converted into the deep green diphenylhydrazido(2,) complexes [Zr(N2TBSNpy)(NNPh2)(py)] (5) and [Hf(N2TBSNpy)(NNPh2)(py)] (6), respectively, by dehydrohalogenation with lithium hexamethyldisilazide (LiHMDS) in the presence of one molar equivalent of pyridine. Both complexes contain a linearly coordinated hydrazinediide for which a DFT-based frontier orbital analysis established bonding through one , and two , orbitals. A high polarity of the MN bond was found, in accordance with the description of hydrazinediide(2,) acting as a six-electron donor ligand. The pyridine ligand in [M(N2TBSNpy)(NNPh2)(py)] (M=Zr: 5, Hf: 6) is substitutionally labile as established by line-shape analysis of the dynamic spectra (,G,=19,kcal,mol,1). A change in denticity of the hydrazido unit from ,1 to ,2 was studied by DFT methods. Both forms are calculated to be very close in energy and are only separated by shallow activation barriers, which supports the notion of a rapid ,1 to ,2 interconversion. This process is believed to happen early on in the NN scission in the presence of coupling reagents. Frontier orbital and natural population analyses suggest that a primarily charge-controlled nucleophilic attack at N, is unlikely whereas interaction with an electrophile could play an important role. This hypothesis was tested by the reaction of 5 and 6 with one molar equivalent of B(C6F5)3 to give [Zr(N2TBSNpy)(NNPh2){B(C6F5)3}] (7) and [Hf(N2TBSNpy)(NNPh2){B(C6F5)3}] (8). In these products, B(C6F5)3 becomes attached to the N, atom of the side-on bound hydrazinediide and there is an additional interaction of an ortho -F atom of a C6F5 ring with the metal centre. [source] Synthesis, Solution-State and Solid-State Structural Characterization of Monocationic Nitrido Heterocomplexes [M(N)(DTC)(PNP)]+ (M = 99Tc, Re; DTC = Dithiocarbamate; PNP = Heterodiphosphane)EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 9 2004Cristina Bolzati Abstract Mono-cationic nitrido heterocomplexes of general formula [M(N)(DTC)(PNP)]+ (where M is 99Tc or Re, DTC is the mono-anionic form of a dithiocarbamate ligand, and PNP is a diphosphane ligand with a tertiary amine-containing five-membered spacer) were prepared by ligand-exchange reactions with the labile precursors [M(N)Cl2(PPh3)2] in dichloromethane/alcohol mixtures. The molecular structure of the representative rhenium complex [Re(N)(dedc)(pnp2)][PF6] (1) displays a distorted, square-pyramidal geometry with the dithiocarbamate sulfur and the diphosphane phosphorus atoms spanning the four coordination positions on the equatorial plane. If the additional interactions between the nitrido nitrogen and the weakly bonded transN -diphosphane heteroatom, the molecular geometry can be viewed as pseudo-octahedral. The structure in solution, as established by multinuclear NMR spectroscopy and ESI spectrometry, is monomeric, and identical to that shown in the solid state. Replacement of the phenyl groups on the phosphorous atoms in complexes 1, 2, 5, and 6 with alkyl groups modified neither the course of the reaction nor the composition of the resulting complexes. These results, together with the observation that no symmetrical complexes containing two identical bidentate ligands were produced in these reactions, strongly supports the conclusion that a mixed coordination sphere, composed by a combination of ,-donor and ,-acceptor atoms around the [M,N]2+ group, constitutes a highly stable system. Compounds containing dangling alkyl-substituted groups in the outer sphere (3, 4, 7, and 8) were fully characterized by multinuclear NMR spectroscopy and ESI mass spectrometry. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004) [source] Structure of a human telomeric DNA sequence stabilized by 8-bromoguanosine substitutions, as determined by NMR in a K+ solutionFEBS JOURNAL, Issue 14 2007Akimasa Matsugami The structure of human telomeric DNA is controversial; it depends upon the sequence contexts and the methodologies used to determine it. The solution structure in the presence of K+ is particularly interesting, but the structure is yet to be elucidated, due to possible conformational heterogeneity. Here, a unique strategy is applied to stabilize one such structure in a K+ solution by substituting guanosines with 8-bromoguanosines at proper positions. The resulting spectra are cleaner and led to determination of the structure at a high atomic resolution. This demonstrates that the application of 8-bromoguanosine is a powerful tool to overcome the difficulty of nucleic acid structure determination arising from conformational heterogeneity. The obtained structure is a mixed-parallel/antiparallel quadruplex. The structure of telomeric DNA was recently reported in another study, in which stabilization was brought about by mutation and resultant additional interactions [Luu KN, Phan AT, Kuryavyi V, Lacroix L & Patel DJ (2006) Structure of the human telomere in K+ solution: an intramolecular (3+1) G-quadruplex scaffold. J Am Chem Soc 128, 9963,9970]. The structure of the guanine tracts was similar between the two. However, a difference was seen for loops connecting guanine tracts, which may play a role in the higher order arrangement of telomeres. Our structure can be utilized to design a small molecule which stabilizes the quadruplex. This type of molecule is supposed to inhibit a telomerase and thus is expected to be a candidate anticancer drug. [source] X-ray crystallographic analysis of the complexes of enoyl acyl carrier protein reductase of Plasmodium falciparum with triclosan variants to elucidate the importance of different functional groups in enzyme inhibitionIUBMB LIFE, Issue 6 2010Koustav Maity Abstract Triclosan, a well-known inhibitor of Enoyl Acyl Carrier Protein Reductase (ENR) from several pathogenic organisms, is a promising lead compound to design effective drugs. We have solved the X-ray crystal structures of Plasmodium falciparum ENR in complex with triclosan variants having different substituted and unsubstituted groups at different key functional locations. The structures revealed that 4 and 2, substituted compounds have more interactions with the protein, cofactor, and solvents when compared with triclosan. New water molecules were found to interact with some of these inhibitors. Substitution at the 2, position of triclosan caused the relocation of a conserved water molecule, leading to an additional hydrogen bond with the inhibitor. This observation can help in conserved water-based inhibitor design. 2, and 4, unsubstituted compounds showed a movement away from the hydrophobic pocket to compensate for the interactions made by the halogen groups of triclosan. This compound also makes additional interactions with the protein and cofactor which compensate for the lost interactions due to the unsubstitution at 2, and 4,. In cell culture, this inhibitor shows less potency, which indicates that the chlorines at 2, and 4, positions increase the ability of the inhibitor to cross multilayered membranes. This knowledge helps us to modify the different functional groups of triclosan to get more potent inhibitors. © 2010 IUBMB IUBMB Life, 467,476, 2010 [source] Tissue engineering of peripheral nerves: Epineurial grafts with application of cultured Schwann cellsMICROSURGERY, Issue 1 2003H. Fansa M.D., Ph.D. After a simple nerve lesion, primary microsurgical suture is the treatment of choice. A nerve gap has to be bridged, with a nerve graft sacrificing a functioning nerve. Alternatively, tissue engineering of nerve grafts has become a subject of experimental research. It is evident that nerve regeneration requires not only an autologous, allogenous, or biodegradable scaffold, but additional interactions with regeneration-promoting Schwann cells. In this study, we compared epineurial and acellularized epineurial tubes with and without application of cultured Schwann cells as alternative grafts in a rat sciatic nerve model. Autologous nerve grafts served as controls. Evaluation was performed after 6 weeks; afterwards, sections of the graft and distal nerve were harvested for histological and morphometrical analysis. Compared to controls, all groups showed a significantly lower number of axons, less well-shaped remyelinizated axons, and a delay in clinical recovery (e.g., toe spread). The presented technique with application of Schwann cells into epineurial tubes did not offer any major advantages for nerve regeneration. Thus, in this applied model, neither the implantation of untreated nor the implantation of acellularized epineurial tubes with cultured Schwann cells to bridge nerve defects was capable of presenting a serious alternative to the present gold standard of conventional nerve grafts for bridging nerve defects in this model. © 2003 Wiley-Liss, Inc. MICROSURGERY 23:72,77 2003 [source] Reversible thermal gelation of soft semi-crystalline polyethylene microparticles with surface interactions in squalanePOLYMER ENGINEERING & SCIENCE, Issue 2 2008Gerald H. Ling The effect of temperature on the steady-shear viscosity of a soft semi-crystalline crosslinked-polyethylene microparticle suspension in squalane was studied using rotational rheometry. The results show a sharp increase in the viscosity of the system occurring at about 86°C. The magnitude of this spike is dependent on the concentration of the suspension and is reproducible over multiple heating and cooling cycles. This phenomenon has been attributed to the melting of the crystalline regions within the particles, causing them to swell by soaking up squalane. The Mooney equation was used to model the viscosity data based on swelling data obtained from separate experiments. The results showed that the model is inadequate for describing the observed phenomenon, suggesting the possibility of additional interactions existing among the particles. POLYM. ENG. SCI., 2008. © 2007 Society of Plastics Engineers [source] Structural characterization of Lyn-SH3 domain in complex with a herpesviral protein reveals an extended recognition motif that enhances binding affinityPROTEIN SCIENCE, Issue 10 2005Finn Bauer Abstract The Src homology 3 (SH3) domain of the Src family kinase Lyn binds to the herpesviral tyrosine kinase interacting protein (Tip) more than one order of magnitude stronger than other closely related members of the Src family. In order to identify the molecular basis for high-affinity binding, the structure of free and Tip-bound Lyn-SH3 was determined by NMR spectroscopy. Tip forms additional contacts outside its classical proline-rich recognition motif and, in particular, a strictly conserved leucine (L186) of the C-terminally adjacent sequence stretch packs into a hydrophobic pocket on the Lyn surface. Although the existence of this pocket is no unique property of Lyn-SH3, Lyn is the only Src family kinase that contains an additional aromatic residue (H41) in the n-Src loop as part of this pocket. H41 covers L186 of Tip by forming tight hydrophobic contacts, and model calculations suggest that the increase in binding affinity compared with other SH3 domains can mainly be attributed to these additional interactions. These findings indicate that this pocket can mediate specificity even between otherwise closely related SH3 domains. [source] Structural basis for the high-affinity binding of pyrrolotriazine inhibitors of p38 MAP kinaseACTA CRYSTALLOGRAPHICA SECTION D, Issue 7 2008John S. Sack The crystal structure of unphosphorylated p38, MAP kinase complexed with a representative pyrrolotriazine-based inhibitor led to the elucidation of the high-affinity binding mode of this class of compounds at the ATP-binding site. The ligand binds in an extended conformation, with one end interacting with the adenine-pocket hinge region, including a hydrogen bond from the carboxyl O atom of Met109. The other end of the ligand interacts with the hydrophobic pocket of the binding site and with the backbone N atom of Asp168 in the DFG activation loop. Addition of an extended benzylmorpholine group forces the DFG loop to flip out of position and allows the ligand to make additional interactions with the protein. [source] Silicon Analogues of the RXR-Selective Retinoid Agonist SR11237 (BMS649): Chemistry and BiologyCHEMMEDCHEM, Issue 7 2009W. Peter Lippert Abstract C/Si switch: Twofold sila-substitution (C/Si exchange) in the RXR-selective retinoids 4,a (SR11237) and 5,a leads to 4,b (disila-SR11237) and 5,b, respectively. Chemistry and biology of the C/Si pairs are reported. SR11237 (BMS649, 4,a) is a pan-RXR-selective retinoid agonist. Its silicon analogue, disila-SR11237 (4,b; twofold C/Si exchange), was prepared in a multistep synthesis by starting from 1,2-bis(ethynyldimethylsilyl)ethane. In addition, the related C/Si analogues 5,a and 5,b, with an indane (disila-indane) instead of a tetraline (disila-tetraline) skeleton, were synthesized. The C/Si pairs 4,a/4,b and 5,a/5,b were studied for their interaction with retinoid receptors and were demonstrated to be highly potent RXR-selective ("rexinoid") agonists. Interestingly, twofold C/Si exchange in the indane moiety of 5,a resulted in a 10-fold increase in biological activity of the corresponding silicon-containing rexinoid 5,b, possibly resulting from an increased receptor affinity or a divergent allosteric effect on co-regulator-binding surfaces. The crystal structures of the ternary complexes formed by 5,a and 5,b, respectively, with the ligand-binding domain of hRXR, and a peptide of the co-activator TIF2/GRIP1 revealed additional interactions of the disila analogue 5,b with the H7 and H11 residues, supporting the first option of increased binding affinity. This is the first demonstration of an increase in binding affinity of a ligand to a nuclear receptor by C/Si replacement, thereby adding this C/Si switch strategy to the repertoire of nuclear receptor ligand design. [source] | ||||||||||