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PubMed1998

RNA as a drug target: chemical, modelling, and evolutionary tools.

Dramatic technical progress in RNA synthesis and structure determination has allowed several difficulties inherent to the preparation, handling and structural analysis of RNA to be overcome, and this has led to a wealth of information about RNA structure and its relationship with biological function. It is now fully recognized that RNA molecules intervene at all stages of cell life, not only because of key sequence motifs but also because of intricate three-dimensional folds. This realization has promoted RNA to a potential therapeutic target. As in protein motifs recognizing nucleic acids, groups of the molecule interacting with RNA contribute to specific binding through defined hydrogen bonds and van der Waals docking, while other parts contribute to the driving force of binding via less specific electrostatic interactions accompanied by water and ion displacement.

Aminoglycosides↗
PubMed1986

Physical-chemical model for the entry of water-insoluble compounds into cells. Studies of fatty acid uptake by the liver.

The spontaneous transfer of water-insoluble substances from plasma to the interior of cells would involve a series of steps in which the substance of interest dissociates from albumin in plasma, enters the outer half of the plasma membrane of a cell, crosses the bilayer, and then dissociates from the inner half of the plasma membrane to enter cell cytosol and diffuses to sites of its metabolism. We have examined the behavior of long-chain fatty acids in the uptake process, assuming that none of these steps is facilitated by the cell during the entry of fatty acids into the liver. Comparison of the spontaneous rates for each individual step with rates of uptake of fatty acid by perfused liver leads to the conclusion that the uptake of fatty acids is not limited by kinetic factors but is determined instead by the equilibrium distribution (Keq) of fatty acids between albumin in plasma and the phospholipids of the plasma membrane. This idea was examined further by determining whether there was a relationship between the value for Keq and rates of uptake of a fatty acid and the pattern of kinetics for uptake. The data indicate that there is a linear relationship between Keq and the rate of uptake, that uptake rates can be predicted with a high degree of accuracy from thermodynamic data, and that the pattern of kinetics of uptake is compatible with the idea that the uptake rate is determined by the relative affinity of a fatty acid for albumin and membranes.

Animals↗
PubMed1987

A physical-chemical model for cellular uptake of fatty acids: prediction of intracellular pool sizes.

If the uptake of fatty acids by liver is a physical, not a biological, process, then the size and location of the intrahepatic pool of fatty acids can be predicted from uptake rates and thermodynamic data. The purpose of the experiments in this paper was to test the accuracy of this idea. Rat livers were perfused with palmitate bound to albumin, and the total amounts of palmitate removed from the perfusate were measured at 3-s intervals. The intrahepatic pools of palmitate calculated from these data were 13.8 and 23.0 nmol/g of liver at ratios of palmitate/albumin (mol/mol) (afferent side) of 2/1 and 4/1, respectively, in the steady state. The intrahepatic pools of palmitate calculated from the distributions of palmitate between membranes, H2O, albumin, and fatty acid binding protein and the measured first-order rate constants for acyl-CoA ligases in mitochondria and microsomes were 12.1 and 34.6 nmol/g for perfusate ratios of palmitate/albumin of 2/1 and 4/1, in the steady state. Intrahepatic pools of palmitate measured after establishment of a steady-state rate of uptake were 15.0 and 31.8 nmol/g for these ratios of palmitate/albumin of 2/1 and 4/1.

Animals↗
PubMed2001

Trapping of an activated HF molecule inside a double four-ring unit: a quantum chemical model of the microporous fluorinated gallium phosphate ULM-18.

The penetration of a proton into the prenucleation building unit of a microporous gallophosphate and its interaction with an encapsulated fluorine anion have been investigated by means of DFT calculations. The inorganic part of the fluorinated gallophosphate ULM-18 has been modeled by a neutral, double four-ring (D4R) unit of formula [(GaOH)4(HPO4)4-H2O] encapsulating the fluorine ion. Assuming the cage to be rigid and to retain throughout the calculations the geometry determined from X-ray diffraction (XRD), the position of F(-) has been optimized, either as an isolated guest species or in the presence of an incoming proton. In agreement with the XRD structure, the fluorine atom has been shown to occupy in both cases a nonsymmetric position in the cage, being attached to three gallium atoms out of four. The distribution of the molecular electrostatic potential inside and outside the (F(-))@[(GaOH)4(HPO4)4-H2O] system has provided indications concerning the pathways that could be used by an incoming proton to penetrate the D4R unit and to approach the fluorine anion. The migration of a proton from an external site of fixation to the interior of the D4R unit has been found possible through two faces out of six. In both cases, the process has been found exothermic by approximately 0.17 eV and the energy barrier was estimated to approximately 0.8 eV. Inside the gallophosphate cage, the proton first adopts a position typical of a strong F...H...O bond made possible through an important shift of the fluorine anion away from the tripod of bonded gallium atoms. Then, the F(-)...H(+) system can easily evolve back and forth on a flat potential curve between one of the F...H...O bonded conformations and a situation characterized by the cleavage of the H...O link and the formation of a moderately activated F-H molecule, with the fluorine still attached to three gallium atoms.

Journal Article↗
PubMed2005

Spectroscopy and quantum chemical modeling reveal a predominant contribution of excitonic interactions to the bathochromic shift in alpha-crustacyanin, the blue carotenoprotein in the carapace of the lobster Homarus gammarus.

To resolve the molecular basis of the coloration mechanism of alpha-crustacyanin, we used (13)C-labeled astaxanthins as chromophores for solid-state (13)C NMR and resonance Raman spectroscopy of [6,6',7,7']-(13)C(4) alpha-crustacyanin and [8,8',9,9',10,10',11,11',20,20']-(13)C(10) alpha-crustacyanin. We complement the experimental data with time-dependent density functional theory calculations on several models based on the structural information available for beta-crustacyanin. The data rule out major changes and strong polarization effects in the ground-state electron density of astaxanthin upon binding to the protein. Conformational changes in the chromophore and hydrogen-bond interactions between the astaxanthin and the protein can account only for about one-third of the total bathochromic shift in alpha-crustacyanin. The exciton coupling due to the proximity of two astaxanthin chromophores is found to be large, suggesting that aggregation effects in the protein represent the primary source of the color change.

Animals↗
PubMed1999

Chemical models of cytochrome P450 catalyzed insecticide metabolism. Application to the oxidative metabolism of carbamate insecticides.

Cytochrome P450 (CP450) catalyzed oxidative metabolism of carbofuran (1), carbaryl (2), and pirimicarb (3) has been modeled using biomimetic oxidations catalyzed by iron(III) tetraarylporphyrins. Oxidation products of 1 were identified by comparison of HPLC retention times measured under standardized conditions for metabolites synthesized and characterized by (1)H and (13)C NMR spectroscopy. Comparison of product distributions to in vivo metabolic profiles revealed that the H(2)O(2)/meso-tetrakis(pentafluorophenyl)porphyrin iron(III) chloride [Fe(TF(20)PP)] system mimics the action of insect CP450s against carbofuran. The effectiveness of this system was further demonstrated by the biomimetic oxidation of other carbamate insecticides (2 and 3) monitored by HPLC/electrospray MS. The predictive power of this biomimetic model was compared to that of knowledge-based expert systems. Although similar models were recently applied in pharmaceutical research, the usefulness of this approach has first been demonstrated for the prediction of metabolic profiles of agrochemicals.

Animals↗
PubMed2006

Quantum chemical modeling of electrochromism of tungsten oxide films.

A cluster model is proposed to describe the excitations in solid tungsten oxide. The density-functional theory approach is used to calculate the ground-state electronic structure of the model cluster and its optimum geometry; subsequently, time-dependent density-functional theory calculations are performed to obtain the oscillator strengths and energies of the excited states. The results are reported both for the electrically neutral cluster and for the cluster with an extra electron (mimicking the effect of electron injection from the cathode). They correctly locate the electrochemically active transition. The corresponding wave functions are delocalized, suggesting that electron localization at one tungsten center is rather unlikely, thereby shedding doubt as to the validity of the polaron model. Local lattice distortions presumably created at the stage of sample preparation are found to affect the excitation energies to a considerable extent, which explains the experimentally observable large width of optical absorption responsible for electrochromism.

Journal Article↗
PubMed1987

A chemical model for the cooperation of sulfates and carboxylates in calcite crystal nucleation: Relevance to biomineralization.

Acidic matrix macromolecules involved in regulation of biological crystal growth often contain aspartic acid-rich domains and covalently bound sulfated polysaccharides. We propose that sulfates and beta-sheet structured carboxylates cooperate in oriented calcite crystal nucleation. The sulfates concentrate calcium, creating the supersaturation necessary for nucleation on the structured carboxylate domains. An artificial model, composed of sulfonated polystyrene surfaces and adsorbed beta-sheet poly(aspartate), demonstrates that the two components indeed act cooperatively with respect to two independent assays, both by induction of calcite nucleation off the (001) plane and by calcium association. Evidence is presented that a purified organic matrix acidic glycoprotein from mollusk shells may behave in vitro in a similar way.

Journal Article↗
PubMed1994

Differences between young and old females in the five levels of body composition and their relevance to the two-compartment chemical model.

BACKGROUND: Body composition differs between young and old females, although the magnitude of these age-related changes remains uncertain. This uncertainty persists because methodology applied in earlier studies required assumptions that may be age-dependent and also because studies included young and old subjects who differed substantially in body size and health status. METHODS: To resolve these earlier concerns we examined components at the atomic, molecular, cellular, tissue-system, and whole body levels of body composition in 19 weight- and height-matched pairs of young (age 19-35 yrs) and old (age > 65 yrs) healthy White females. Isotope dilution, dual photon, whole-body counting, hydrodensitometry, and anthropometric methods were used either alone or in combination to produce multicomponent models. RESULTS: Old females had significantly more fat, greater truncal skinfolds and circumferences, and significantly less fat-free body mass (FFM), total body potassium (TBK), total body water (TBW), and bone mineral than did their young matched counterparts. Skeletal muscle mass was less in the old females, although the magnitude of the difference from young females varied between the three indices examined. The main assumptions (i.e., TBW/FFM = 0.73 kg/kg and density of FFM = 1.100 g/cc) which the widely used two-compartment TBW and hydrodensitometry methods are based on were not significantly different in young and old females. In contrast, the main assumed steady-state value for the two-compartment TBK method (TBK/FFM = 64.2 mmol/kg) was significantly lower (p < .001) in the old females. CONCLUSION: New approaches thus allow for a critical reexamination of body composition in elderly subjects, and these methods also give new insight into less complex widely used body composition techniques.

Adipose Tissue↗
PubMed1984

Perilla ketone toxicity: a chemical model for the study of equine restrictive lung disease.

Perilla ketone was assessed for its usefulness as a model of equine restrictive pulmonary disease. Three ponies were given 18 mg/kg bodyweight synthetic perilla ketone in dimethyl-sulphoxide. Within 24 h of administration, respiratory rate, peak inspiratory and expiratory flow rates and minute volume were increased. By 48 h there was a significant decrease in tidal volume, and blood pH and base excess were also decreased but not outside normal limits. At necropsy there was congestion and oedema of the lungs. Histologically there was diffuse alveolar injury but no evidence of significant obstruction in bronchial or bronchiolar lumina. It is assumed that perilla ketone toxicity in ponies produces a restrictive disease without a significant obstructive component.

Animals↗
PubMedDate not supplied

Quantum-chemical model evaluations of thermodynamics and kinetics of oxygen atom additions to narrow nanotubes.

This paper reports a computational study of oxygen additions to narrow nanotubes, a problem frequently studied with fullerenes. In fact, fullerene oxides were the first observed fullerene derivatives, and they have naturally attracted the attention of both experiment and theory. C60O had represented a long-standing case of experiment-theory disagreement, and there has been a similar problem with C60O2. The disagreement has been explained by kinetic rather than thermodynamic control. In this paper a similar computational approach is applied to narrow nanotubes. Recently, very narrow nanotubes have been observed with a diameter of 5 A and even with a diameter of 4 A. It has been supposed that the narrow nanotubes are closed by fragments of small fullerenes like C36 or C20. In this report we perform calculations for oxygen additions to such model nanotubes capped by fragments of D2d C36, D4d C32, and Ih C20 fullerenic cages (though the computational models have to be rather short). The three models have the following carbon contents: C84, C80, and C80. Both thermodynamic enthalpy changes and kinetic activation barriers for oxygen addition to six selected bonds are computed and analyzed. The lowest isomer (thermodynamically the most stable) is never of the 6/6 type, that is, the enthalpically favored structures are produced by oxygen additions to the nanotube tips. Interestingly enough, the lowest energy isomer has, for the D2d C36 and D4d C32 cases, the lowest kinetic activation barrier as well.

Computer Simulation↗
PubMed2001

[The mechanism of action of isoniazid. A chemical model of activation].

The antituberculosis drug isoniazid (INH) is quickly oxidized by stoichiometric amounts of manganese(III)-pyrophosphate. In the presence of the nicotinamide coenzyme, the INH oxidation produced the formation of INH-NAD(H) adducts which are potential competitive inhibitors of the enoyl-acyl carrier protein reductase InhA, an INH target in the biosynthetic pathway for mycolic acids. Manganese(III)-pyrophosphate is an efficient alternative oxidant to mimick the activity of the Mycobacterium tuberculosis KatG catalase-peroxidase and will be useful for further mechanistic studies of INH activation and for structural investigations on reactive INH species and resulting InhA inhibitors.

Antitubercular Agents↗
PubMed1978

Effects of sensitizers on cell respiration: II. The effects of hypoxic cell sensitizers on oxygen utilization in cellular and chemical models.

The metabolic activity of nitroheterocyclic sensitizers could limit their usefulness in vivo. Biochemical mechanisms of drug metabolism, toxicity and effects on cell respiration have been studied in microsomes, and the kinetics of the simulated redox reactions determined by pulse radiolysis. Stimulated oxidation of coenzyme, glucose, ascorbate or glutathione substrate radicals by nitroheterocyclic sensitizers, with the concomitant appearance of the respective nitro radical anions, is observed. Under hypoxia, the nitro radical anions decay slowly by second order processes, forming reduced metabolites. In air, the nitro radical anions react with oxygen forming superoxide radical anions, peroxide and regenerating the drug. Nitro radical-anions also react with cytochrome-c indicating a possible interference with mitochondrial energy metabolism.

Animals↗
PubMed1988

[Amyotrophic lateral sclerosis. Physiopathology and experimental models. Chemical neuroanatomy of the human spinal cord: applications to pathologic cases including amyotrophic lateral sclerosis].

The purpose of this paper is to illustrate the advantages of the chemo-morphological approach in the study of pathological material. On one hand, the analysis of selected pathological cases (amputations, spinal transections) is able to provide invaluable information concerning the cells of origin of certain spinal transmitters in the human being. On the other hand, chemical neuropathology allows a more precise identification of the neuronal nets or types that are involved in a disease process. This advantage is underlined by studies performed in amyotrophic lateral sclerosis. In this condition, certain modifications, such as the reductions of acetylcholinesterase, choline acetyltransferase, cholinergic muscarinic, glycine or TRH receptors, are probably a consequence of motoneuron degeneration. In contradistinction, other findings, such as specific metabolic changes of motoneurons or early disappearance of SP-containing fibers in lamina IX, might be relevant for the pathogenesis of the disease.

Amyotrophic Lateral Sclerosis↗