Mechanistic aspects of biological redox reactions involving NADH 2: A combined semiempirical and ab initio study of hydride-ion transfer between the NADH analogue, 1-methyl-dihydronicotinamide,and folate and dihydrofolate analogue substrates of dihydrofolate reductase

As part of a study of factors controlling biological redox reactions of nicotinamide cofactors [nicotinamide adenine dinucleotide (phosphate) NAD(P)H], we have investigated the effect on a model reaction of the conformational state (cis or trans) of the carboxamide side chain, using quantum chemical methods. The reaction is that for the enzyme dihydrofolate reductase between the NADPH analogue, 1-methyl-dihydronicotinamide, and the protonated forms of the folate and dihydrofolate substrate analogues, pyrazine and dihydropyrazine. Some calculations on pterin and dihydropterin substrate analogues were also carried out in order to gauge the effects of inter-ring coupling. The influence of carboxamide side-chain conformation of nicotinamide on the energetics of the hydride-ion transfer, and on the structures of the transition states and stable intermolecular-interaction complexes, are examined as a function of the orientation of approach of the reactants. These approach geometries include those corresponding to the observed binding of cofactor and either substrate or inhibitor in the enzyme active site. Reactant, product, reactants-complex, and transition-state geometries were optimized at the semiempirical AM1 level, while ab initio SCF/STO-3G and SCF/3-21G single-point calculations were carried out at the AM1 optimized geometries for all species, as well as full geometry optimizations for isolated reactants and products. The results show that reactants-complex and transition-state energies are lower for the trans conformer of dihydronicotinamide than for the cis conformer, due to more favorable H-bonding or electrostatic interactions with the protonated substrate. Also, consideration of the structural parameters, including reaction coordinate bond lengths, ring geometries, and charge distributions, indicate that the trans transition states are more product-like than those for the cis. For the (trans) approaches corresponding to the enzymic orientation for substrate, the intermolecular interaction for the folate reaction lacks the stabilizing influence of the formal H-bond which is present for the dihydrofolate reaction, and consequently the reactants-complex and transition state are less stable.     

Compound prioritization methods increase rates of chemical probe discovery in model organisms

Preselection of compounds that are more likely to induce a phenotype can increase the efficiency and reduce the costs for model organism screening. To identify such molecules, we screened ~81,000 compounds in Saccharomyces cerevisiae and identified ~7500 that inhibit cell growth. Screening these growth-inhibitory molecules across a diverse panel of model organisms resulted in an increased phenotypic hit-rate. These data were used to build a model to predict compounds that inhibit yeast growth. Empirical and in silico application of the model enriched the discovery of bioactive compounds in diverse model organisms. To demonstrate the potential of these molecules as lead chemical probes, we used chemogenomic profiling in yeast and identified specific inhibitors of lanosterol synthase and of stearoyl-CoA 9-desaturase. As community resources, the ~7500 growth-inhibitory molecules have been made commercially available and the computational model and filter used are provided.     

直接键连原子间的NMR偶合常数的自然杂化轨道研究V.~(13)C-~(13)C和~(13)C-~(31)P核自旋偶合常数~1J_(CC)和~1J_(CP)

在前文工作的基础上，结合ＭＮＤＯ／ＥＨＭＯ分子轨道方法和自然杂化轨道方法，具体计算了ＣＣ键和ＣＰ键的核自旋偶合常数．计算结果表明，１ＪＣＣ和１ＪＣＰ主要由成键原子的轨道杂化作用和键极性这两种结构因素所决定．为从简单价键理论角度解释和计算１ＪＣＣ和１ＪＣＰ值提供了简便直观的方法．     

Mechanism of white phosphorus activation by three-coordinate molybdenum(III) complexes: a thermochemical, kinetic, and quantum chemical investigation

White phosphorus (P(4)) reacts with three-coordinate molybdenum(III) trisamides or molybdaziridine hydride complexes to produce either bridging or terminal phosphide (P(3)(-)) species, depending upon the ancillary ligand steric demands. Thermochemical measurements have been made that place the MoP triple bond dissociation enthalpy at 92.2 kcal.mol(-)(1). Thermochemical measurements together with computational analysis rule out simple P-atom abstraction from P(4) as a step in the phosphorus activation mechanism. Kinetic measurements made by the stopped-flow method show that the reaction between the monomeric molybdenum complexes and P(4) is first-order both in metal complex and in P(4). Cyclo-P(3) complexes can be obtained when ancillary ligand steric demands are small, but kinetic measurements rule them out as monometallic intermediates in the P(4) activation mechanism. Also studied by calorimetric, kinetic, and in one case variable-temperature NMR methods is the process of mu-phosphide bridge formation. Post-rate-determining steps of the P(4) activation process were examined in a search for minima on the reaction's potential energy surface, leading to the proposal of two plausible, parallel, bimetallic reaction channels.     

6-Coordinate tungsten(VI) tris-n-isopropylanilide complexes: products of terminal oxo and nitrido transformations effected by main group electrophiles

The nitridotungsten(vi) complex NW(N[i-Pr]Ar)(3) (-N, Ar = 3,5-Me(2)C(6)H(3)) reacts with (CF(3)C(O))(2)O followed by ClSiMe(3) to give the isolable trifluoroacetylimido-chloride complex -(NC(O)CF(3))Cl, with oxalyl chloride to give cyanate-dichloride -(OCN)(Cl)(2), and with PCl(5) to give trichlorophosphinimide-dichloride -(NPCl(3))(Cl)(2). The oxo-chloride complex -(O)Cl, obtained from -N upon treatment with pivaloyl chloride, reacts with PCl(5) to give trichloride -(Cl)(3). Synthetic and structural details are reported for the new tungsten trisanilide derivatives.