Abstract. A novel evodiamine (EVO)-phospholipid complex (EPLC) was designed to improve the bioavailability of EVO. A central composite design approach was employed for process optimization. EPLC were characterized by differential scanning calorimetry, ultraviolet spectroscopy, Fourier transformed infrared spectroscopy, 1 H-NMR spectroscopy, matrix-assisted laser desorption/ionization time-offlight spectroscopy, apparent solubility, and dissolution rate. After oral administration of EPLC, the concentrations of EVO at different time points were determined by high-performance liquid chromatography. The optimal formulation for EPLC was obtained where the values of X 1 , X 2 , and X 3 were 2, 0.5, and 2.5 mg/mL, respectively. The average particle size and zeta potential of EPLC with the optimized formulation were 246.1 nm and −26.94 mV, respectively. The EVO and phospholipids in the EPLC were associated with non-covalent interactions. The solubility of EPLC in water and the dissolution rate of EPLC in phosphate-buffered solution (pH 6.8) were substantially enhanced. The plasma EVO concentration-time curves of EPLC and free EVO were both in accordance with the two-compartment model. The peak concentration and AUC 0−∞ of EPLC were increased, and the relative bioavailability was significantly increased to 218.82 % compared with that of EVO.
Direct dynamics calculations employing hybrid quantum mechanical and molecular mehanical (QM/MM) potentials and molecular dynamics simulation methods have been used to explore the important dynamic role that enzyme structure has on proton transfer in the C-H bond breakage of a methylamine substrate by methylamine dehydrogenase (MADH). Canonical variational transition state theory with optimised multidimensional tunnelling corrections has been used to predict deuterium kinetic isotope effects corresponding to a range of enzyme conformations and to show the importance of donor acceptor separation, and transition state and product stabilisation within the active site. Large kinetic isotope effects can be predicted for proton transfer with both semi-empirical and ab initio electronic structure methods.
2003) Extreme tunnelling in methylamine dehydrogenase revealed by hybrid QM/MM calculations: potential energy surface profile for methylamine and ethanolamine substrates and kinetic isotope effect values,The rate-determining proton transfer step in the amine reduction reaction catalysed by the enzyme methylamine dehydrogenase has been studied using a hybrid quantum mechanical/ molecular mechanical (QM/MM) model. Variational transition state theory, combined with multidimensional tunnelling corrections, has been employed to calculate reaction rate constants, and hence deuterium kinetic isotope effects (KIE). To render these calculations computationally feasible, the electronic structure was described using a PM3 method with specific reaction parameters obtained by a fit to energetics obtained at a high level for a small model system. Compared to the use of standard parameters, these revised parameters result in a considerable improvement in the predicted KIE values and activation energy. For both methylamine and ethanolamine substrates, through-barrier, rather than over-barrier, motion is found to dominate with KIE values that are large and close to the experimental values. A major difference between the two substrates is that, for ethanolamine, different hydrogen bonding structures involving the substrate hydroxyl are possible, leading to very different potential energy surfaces with KIE values covering a considerable range. We speculate that this is the origin of the differing temperature behaviour observed for the KIEs of the two substrates.
As part of a study of species important in automotive exhaust chemistry, the reactivity of atomic N and NO on Pt͑335͒ at low temperature has been studied. The atomic N was produced by dissociating adsorbed NO with a 76 eV electron beam. Cross sections for electron-stimulated desorption and dissociation are estimated for NO on terrace and step sites. Terrace NO is at least five times more likely to desorb than to dissociate.Step NO has a lower desorption cross section than terrace NO, but probably a higher dissociation cross section. Temperature-programmed desorption was used to monitor desorption, dissociation, and the formation of N 2 and N 2 O from adsorbed N and NO. Five distinct desorption states of N 2 formed by NO dissociation are identified. The dominant N 2 peak ͑435 K͒ comes from electron-dissociated step NO; its desorption temperature is higher than the N 2 peaks from electron-dissociated terrace NO. Coadsorbed N and NO react to form N 2 O even below 100 K, with an activation barrier of ϳ6 kcal/mol. Only terrace NO participates in this reaction; step NO does not react to form N 2 O. This site dependence resembles that for CO oxidation on Pt͑112͒ and Pt͑335͒ and can be rationalized with simple steric considerations. All of the forms of atomic N participate in N 2 O formation, but that formed by the dissociation of step NO exhibits the lowest reaction temperature. Hence, the same N atoms that only recombine to form N 2 at 435 K, react with NO to form N 2 O at 100 K. We found no evidence for an NO reaction with N atoms to form N 2 and adsorbed O, or for NO formation from the recombination of adsorbed N and adsorbed O 2 .
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