Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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An extensive theoretical study of the stereoisomers of tetrahydrocannabinols has been performed at the ab initio HF/6-31G* and B3LYP/6-31G* levels. Effects of solvation were calculated with the Onsager model (with full geometry optimization), SCRF with Tomasi's PCM, and isodensity polarization continuum models. Single-point MP2//HF/6-31G* calculations were carried out. Frequency calculations for all the isomers at the HF/6-31G* level and for two natural isomers delta1-THC-RR and delta6-THC-RR at the B3LYP/6-31G* level were performed. Our results support the findings of the previous AM1 studies that the orientation of the carbocyclic ring and its C1 substituent with respect to the phenyl group hydroxyl oxygen play the major role in the activity. The calculated values of the LUMO energy (lowest unoccupied molecular orbital) and the hardness of the stereoisomers show that for the trans isomers it is easier to remove one electron from its HOMO (highest occupied molecular orbital) to the LUMO and easier to accept an electron from the receptor binding site than for the cis isomers. Combining geometric features (the orientation of the carbocyclic ring and its C1 substituent with respect to the phenyl group hydroxyl oxygen) with electronic features (LUMO and hardness), we explain the activity differences among the stereoisomers.
J Comput Aided Mol Des 2001 Apr
PMID:An ab initio theoretical study of the stereoisomers of tetrahydrocannabinols. 1134 15

In rats with protein-calorie malnutrition (PCM, 5% caseine diet for 4 weeks), hepatic cytochrome P450 levels suppressed markedly and cytochrome P450 mRNAs decreased significantly compared with those in control rats (23% caseine diet for 4 weeks), however, the values completely (or partially) returned to control levels by a week (from fourth week) of cysteine supplementation (rats with PCMC) (Cho, Kim et al., Arch. Biochem. Biophys. 1999, 372: 150-158). The formation of aglycone metabolites of adriamycin and adriamycinol, M3 and M4, respectively, seemed to be induced (Lee and Lee, Res. Commun. Mol. Pathol. Pharmacol. 1999, 105: 87-96) by pretreatment with dexamethasone (possibly by hepatic cytochrome P450 RL 33/cDEX, Komori and Oda, J. Biochem. 1994, 116: 114-120) in rats. Adriamycin, 16 mg/kg, was administered intravenously in 1-min to control rats and rats with PCM and PCMC. In rats with PCM, the plasma concentrations of adriamycin was higher (the area under the plasma concentration-time curve from time zero to 12 hr, AUC(0-12 hr), tended to be higher) and 24-hr urinary excretion of M3 (including its 'conjugates') seemed to increase than those in control rats, suggested that the formation of M3 was inhibited in rats with PCM. In rats with PCMC, the plasma concentrations of adriamycin were lower (the AUC(0-12 hr) was significantly smaller) and 24-hr urinary excretion of M3 (including its 'conjugates') were significantly greater than those in rats with PCM, suggested that the formation of M3 increased significantly by cysteine supplementation by restoring the enzyme system(s) that metabolize adriamycin to M3. The altered pharmacokinetic parameters of adriamycin mentioned above in rats with PCM returned to greater than those of control rats after cysteine supplementation (rats with PCMC). Above data suggested that other hepatic cytochrome P450 isozyme(s) which catalyze(s) the formation of M3 from adriamycin could be induced by cysteine supplementation.
Res Commun Mol Pathol Pharmacol
PMID:Effects of cysteine on the pharmacokinetics of intravenous adriamycin in rats with protein-calorie malnutrition. 1158 63

Experimental and theoretical structural studies of 5-amino-3-methylisoxazolo-4-carboxylic acid p-chlorophenylamide were performed. This compound belongs to a new class of isoxazole derivatives exhibiting promising immunological activity. The crystallographic structure was measured and compared with theoretical calculations for the investigated compound. The theoretical analyses were performed using Kohn-Sham density functional theory (DFT) with the B3LYP hybrid exchange-correlation energy functional and 6-311+G(d,p) basis set. The solvent effect was included using the SCRF/PCM method with water (epsilon=78) as a solvent. Topological analysis was performed in terms of Bader's theory of atoms in molecules, yielding molecular parameters for quantum molecular similarity investigations. Figure The SCRF/PCM map of electrostatic potential around the molecule: light grey isosurface at +0.5 a.u., dark grey at -0.05 a.u.
J Mol Model 2003 Jun
PMID:An experimental and theoretical structural study of 5-amino-3-methylisoxazolo-4-carboxylic acid p-chlorophenylamide. 1268 35

The effects of cysteine on the pharmacokinetics of azosemide were investigated after intravenous administration of drug, 10 mg/kg, to male Sprague-Dawley rats pretreated with 3-methylcholanthrene fed on 23% protein diet (control rats) and 5% protein diet without (rats with protein-calorie malnutrition, PCM) or with (rats with PCMC) oral cysteine (250 mg/kg, twice daily starting from the fourth week) for 4 weeks. After intravenous administration to rats with PCM, the metabolites of azosemide excreted in urine and recovered from gastrointestinal tract decreased significantly than those in control rats, however, the plasma concentrations, total area under plasma concentration-time curve from time zero to time infinity (AUC) and time-averaged total body clearance (CL) were not significantly different between two groups of rats. It was reported that after intravenous administration of azosemide, 10 mg/kg, to rats with PCMC without pretreatment 3-methylcholanthrene, some pharmacokinetic parameters restored fully or more than the level of control rats; the time-averaged nonrenal clearance and apparent volume of distribution at steady state were comparable to those in control rats, but the terminal half-life and mean residence time were significantly shorter, AUC was significantly smaller, and time-averaged renal clearance and CL were significantly faster than those in control rats. However, the above mentioned effects of cysteine on the pharmacokinetic parameters of azosemide in rats with PCM were not observed with pretreatment with 3-methylcholanthrene.
Res Commun Mol Pathol Pharmacol 2001
PMID:No effect of cysteine on the pharmacokinetics of intravenous azosemide in rats with protein-calorie malnutrition by pretreatment with 3-methylcholanthrene. 1288 26

One approach to targeted therapies for cardiovascular disease relies on isolating ligands that enhance the tissue-specific uptake of genes or drugs by heart cells. To obtain heart-targeting ligands, phage display biopanning was used to isolate a 20-mer peptide that binds to isolated primary cardiomyocytes. The isolated phage, PCM.1, displays the peptide WLSEAGPVVTVRALRGTGSW, and binds these cells 180 times better than a control phage from the library. Furthermore, phage displaying this peptide preferentially bind to cardiomyocytes when compared with a panel of other cell types. A BLAST search revealed that this peptide contains a 12 amino acid segment with sequence identity to a peptide in tenascin-X, an extracellular matrix protein. Synthetic peptides containing the complete 20-mer or a 12-mer tenascin peptide partially blocked phage binding to the cardiomyocytes. We developed a quantitative real-time PCR assay to assess uptake of this phage by tissues in vivo. Using this assay, preferential localization of the PCM.1 phage in heart was observed compared to the uptake of this phage by other tissues or other phage by heart. Furthermore, PCM.1 phage was associated with cardiomyocytes isolated from mice treated with a phage in vivo. These results demonstrate the utility of biopanning on isolated cells for identifying specific binding peptides that can target a tissue in vivo.
J Mol Biol 2004 Sep 03
PMID:In vitro selection of a peptide with high selectivity for cardiomyocytes in vivo. 1531 15

This work outlines a new on-line database of quantum calculations for RNA catalysis (QCRNA) available via the worldwide web at http://theory.chem.umn.edu/QCRNA. The database contains high-level density functional calculations for a large range of molecules, complexes and chemical mechanisms important to phosphoryl transfer reactions and RNA catalysis. Calculations are performed using a strict, consistent protocol such that a wealth of cross-comparisons can be made to elucidate meaningful trends in biological phosphate reactivity. Currently, around 2000 molecules have been collected in varying charge states in the gas phase and in solution. Solvation was treated with both the PCM and COSMO continuum solvation models. The data can be used to study important trends in reactivity of biological phosphates, or used as benchmark data for the design of new semiempirical quantum models for hybrid quantum mechanical/molecular mechanical simulations.
J Mol Graph Model 2006 Dec
PMID:QCRNA 1.0: a database of quantum calculations for RNA catalysis. 1658 Aug 53

B3LYP/6-31G* and 6-311++G** calculations have been carried out in order to study the hydration of phosphates in aqueous media. Optimized geometries and relative stabilities for PO4(-3), HPO(4)-2, H2PO4(-1) have been calculated considering the interaction with one, two, three, four and five discrete water molecules and taking into account the solvent effect by using the self-consistent reaction field theory (Onsager and PCM methods). The role of specific and bulk contributions of solvent effect on the observable properties of phosphate compounds is analysed. Good agreement between theoretical and available experimental results of harmonic vibration frequencies is found. Significant effects on the geometrical and vibrational frequencies are found for those studied phosphate anions. The results presented here provide a first step toward the understanding of the phosphate group as a hydration sensor in lipid bilayers.
Spectrochim Acta A Mol Biomol Spectrosc 2007 Apr
PMID:Hydration of inorganic phosphates in crystal lattices and in aqueous solution. An experimental and theoretical study. 1684 15

Resonance Raman (RR) spectra of green fluorescent protein (GFP) model chromophores in solution have been simulated with the CASSCF/MM methodology. Although several reports on vibrational analysis of GFP model chromophores have been recently published, the RR spectra were simulated for the first time in explicit solution with the inclusion of the counterion, as these effects are crucial for unambiguously reproducing the vibrational band assignment in the anionic form of the GFP chromophore. This strategy allows for a one-to-one correspondence of the calculated vibrational modes to the observed RR bands, concerning both the location and intensity pattern. In addition, these simulations were complemented with total energy distribution calculations to aid in the unambiguous assignment of the measured spectra. The current study helps to clarify some of the previous RR bands assignments as well as producing some new assignment for the anionic form of GFP chromophore. The explicit solvent simulations and PCM-based calculations are compared to the measured spectra, and these results demonstrate that explicit solvent simulations provide better agreement with experiment, both in terms of vibrational frequencies and intensity distribution.
J Mol Model 2007 Jul
PMID:Vibrational analysis of a solvated green fluorescent protein chromophore. 1738 Mar 52

The metabolism mechanism of (S)-N-[1-(3-morpholin-4ylphenyl)ethyl]-3-phenylacrylamide, mediated by CYP3A4 Cytochrome has been investigated by density functional QM calculations aided with molecular mechanics/molecular dynamics simulations. Two different orientations of phenyl ring for substrate approach toward oxyferryl center, imposing two subsequent rearrangement pathways have been investigated. Starting from sigma-complex in perpendicular orientation enzymatic mechanism involves consecutive proton shuttle intermediate, which further leads to the formation of alcohol and ketone. Parallel conformation leads solely to ketone product by 1,2 hydride shift. Although parallel and perpendicular sigma-complexes are energetically equivalent both for the gas phase or PCM solvent model, molecular dynamics studies in full CYP3A4 environment show that perpendicular conformation of the sigma-complex should be privileged, stabilized by hydrophobic interactions of phenylacrylamide chain. After assessing probability of the two conformations we postulate that the alcohol, accessible with the lowest energy barriers should be the major metabolite for studied substrate and CYP3A4 enzyme.
J Mol Model 2007 Jul
PMID:Oxidation mechanism in the metabolism of (S)-N-[1-(3-morpholin-4-ylphenyl)ethyl]-3-phenylacrylamide on oxyferryl active site in CYP3A4 Cytochrome: DFT modeling. 1738 27

Erigeroside was extracted from Satureja khuzistanica Jamzad (Marzeh Khuzistani in Persian, family of lamiaceae), and (1)H, (13)C, (13)C{(1)H}, (1)H-(1)H COSY, HMQC and J-HMBC were obtained to identify this compound and determine a complete set of J-coupling constants ((1)J(C-H), (2)J(C-H), (3)J(C-H) and (3)J(H-H)) values within the exocyclic hydroxymethyl group (CH(2)OH) and anomeric center. In parallel, density functional theory (DFT) using B3LYP functional and split-valance 6-311++G** basis set has been used to optimized the structures and conformers of erigeroside. In all calculations solvent effects were considered using a polarized continuum (overlapping spheres) model (PCM). The dependencies of (1)J, (2)J and (3)J involving (1)H and (13)C on the C(5')-C(6') (omega), C(6')-O(6') (theta) and C(1')-O(1') (phi) torsion angles in erigeroside were computed using DFT method. Complete hyper surfaces for (1)J(C1',H1'), (2)J(C5',H6'R), (2)J(C5',H6'S), (2)J(C6',H5'), (3)J(C4',H6'R), (3)J(C4',H6'S) and (2)J(H6'R-H5'S) as well as (3)J(H5',H6'R) were obtained and used to derive Karplus equations to correlate these couplings to omega, theta and phi. These calculated J-couplings are in agreement with experimental values. These results confirm the reliability of DFT calculated coupling constants in aqueous solution.
Spectrochim Acta A Mol Biomol Spectrosc 2008 Jul
PMID:Dynamic stereochemistry of erigeroside by measurement of 1H-1H and 13C-1H coupling constants. 1808 14


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