Relationships Between Pharmacovigilance, Molecular, Structural, and Pathway Data: Revealing Mechanisms for Immune-Mediated Drug-Induced Liver Injury.

Immune-mediated drug-induced liver injury (IMDILI) can be devastating, irreversible, and fatal in the absence of successful transplantation surgery. We present a novel approach that combines the methods of pharmacoepidemiology with in silico molecular modeling to identify specific features in toxic ligands that are associated with clinical features of IMDILI. Specifically, from pharmacovigilance data multivariate logistic regression identified 18 drugs associated with IMDILI (P < 0.00015). Eleven of these drugs, along with their known and proposed metabolites, constituted a training set used to develop a four-point pharmacophore model (sensitivity 75%; specificity 85%). Subsequently, this information was combined with information from immune-pathway reviews and genetic-association studies and complemented with ligand-protein docking simulations to support a hypothesis implicating two putative targets within separate, possibly interacting, immune-system pathways: the major histocompatibility complex within the adaptive immune system and Toll-like receptors (TLRs), in particular TLR-7, which represent pattern recognition receptors of the innate immune system.

Corticosteroids and ß2-agonists upregulate mitogen-activated protein kinase phosphatase 1: in vitro mechanisms.

BACKGROUND AND PURPOSE: Airway remodelling is a consequence of long-term inflammation and MAPKs are key signalling molecules that drive pro-inflammatory pathways. The endogenous MAPK deactivator--MAPK phosphatase 1 (MKP-1)--is a critical negative regulator of the myriad pro-inflammatory pathways activated by MAPKs in the airway. EXPERIMENTAL APPROACH: Herein we investigated the molecular mechanisms responsible for the upregulation of MKP-1 in airway smooth muscle (ASM) by the corticosteroid dexamethasone and the ß2-agonist formoterol, added alone and in combination. KEY RESULTS: MKP-1 is a corticosteroid-inducible gene whose expression is enhanced by long-acting ß2-agonists in an additive manner. Formoterol induced MKP-1 expression via the ß2-adrenoceptor and we provide the first direct evidence (utilizing overexpression of PKIα, a highly selective PKA inhibitor) to show that PKA mediates ß2-agonist-induced MKP-1 upregulation. Dexamethasone activated MKP-1 transcription in ASM cells via a cis-acting corticosteroid-responsive region located between -1380 and -1266 bp of the MKP-1 promoter. While the 3'-untranslated region of MKP-1 contains adenylate + uridylate elements responsible for regulation at the post-transcriptional level, actinomycin D chase experiments revealed that there was no increase in MKP-1 mRNA stability in the presence of dexamethasone, formoterol, alone or in combination. Rather, there was an additive effect of the asthma therapeutics on MKP-1 transcription. CONCLUSIONS AND IMPLICATIONS: Taken together, these studies allow us a greater understanding of the molecular basis of MKP-1 regulation by corticosteroids and ß2-agonists and this new knowledge may lead to elucidation of optimized corticosteroid-sparing therapies in the future.

Novel properties from experimental charge densities: an application to the zwitterionic neurotransmitter taurine.

The charge distribution of taurine (2-aminoethane-sulfonic acid) is revisited by using an orbital-based method that describes the density in a fixed molecular orbital basis with variable orbital occupation numbers. A new neutron data set is also employed to explore whether this improves the deconvolution of thermal motion and charge density. A range of molecular properties that are novel for experimentally determined charge densities are computed, including Weinhold population analysis, Mayer bond orders, and local kinetic energy densities, in addition to charge topological analysis and quantum theory of atoms-in-molecules (QTAIM) integrated properties. The ease with which a distributed multipole analysis can be performed on the fitted density matrix makes it straightforward to compute molecular moments, the lattice energy, and the electrostatic interaction energies of molecules removed from the crystal. Results are compared with high-level (QCISD) gas-phase calculations and band structure calculations employing density functional theory. Finally, the avenues available for extending the range of molecular properties that can be calculated from experimental charge densities still further using this approach are discussed.

Calculation of the hydrophobicity of platinum drugs.

Models of the hydrophobicity of platinum drugs based on exposed surface areas of polar and nonpolar atoms are presented. For a total of 24 log P(oct) data, the best model resulted in a standard deviation of 0.35 over a range of more than 4 log units, with regression coefficients in broad agreement with previous models of log P(oct) for organic molecules. This model is used to compare log P(oct) to cell uptake for five platinum drugs and hence to establish an exponential relation between these parameters.

Crystal chemistry and physical properties of superconducting and semiconducting charge transfer salts of the type (BEDT-TTF)(4)[A(I)M(III)(C2O4)3]*PhCN (A(I) = H30,NH4,K; M(III) = Cr, Fe, Co, Al; BEDT-TTF = bis(ethylenedithio)tetrathiafulvalene.

Synthesis, structure determination by single-crystal X-ray diffraction, and physical properties are reported and compared for superconducting and semiconducting molecular charge-transfer salts with stoichiometry (BEDT-TTF)(4)[A(I)M(III)(C(2)O(4))(3)].PhCN, where A(I) = H(3)O, NH(4), K; M(III) = Cr, Fe, Co, Al; BEDT-TTF = bis(ethylenedithio) tetrathiafulvalene. Attempts to substitute M(III) with Ti, Ru, Rh, or Gd are also described. New compounds with M = Co and Al are prepared and detailed structural comparisons are made across the whole series. Compounds with A = H(3)O(+) and M = Cr, Fe are monoclinic (space group C2/c), at 150, 120 K a = 10.240(1) A, 10.232(12) A; b = 19.965(1) A, 20.04(3) A; c = 34.905(1) A, 34.97(2) A; beta = 93.69(1) degrees, 93.25(11) degrees, respectively, both with Z = 4. These salts are metallic at room temperature, becoming superconducting at 5.5(5) or 8.5(5) K, respectively. A polymorph with A = H(3)O(+) and M = Cr is orthorhombic (Pbcn) with a = 10.371(2) A, b = 19.518(3) A, c = 35.646(3) A, and Z = 4 at 150 K. When A = NH(4)(+), M = Fe, Co, Al, the compounds are also orthorhombic (Pbcn), with a = 10.370(5) A, 10.340(1) A, 10.318(7) A; b = 19.588(12) A, 19.502(1) A, 19.460(4) A; c = 35.790(8) A, 35.768(1) A, 35.808(8) A at 150 K, respectively, with Z = 4. All of the Pbcn phases are semiconducting with activation energies between 0.15 and 0.22 eV. For those compounds which are thought to contain H(3)O(+), Raman spectroscopy or C=C and C-S bond lengths of the BEDT-TTF molecules confirm the presence of H(3)O(+) rather than H(2)O. In the monoclinic compounds the BEDT-TTF molecules adopt a beta' ' packing motif while in the orthorhombic phases (BEDT-TTF)(2) dimers are surrounded by monomers. Raman spectra and bond length analysis for the latter confirm that each molecule of the dimer has a charge of +1 while the remaining donors are neutral. All of the compounds contain approximately hexagonal honeycomb layers of [AM(C(2)O(4))(3)] and PhCN, with the solvent occupying a cavity bounded by [M(C(2)O(4))(3)](3-) and A. In the monoclinic series each layer contains one enantiomeric conformation of the chiral [M(C(2)O(4))(3)](3-) anions with alternate layers having opposite chirality, whereas in the orthorhombic series the enantiomers form chains within each layer. Analysis of the supramolecular organization at the interface between the cation and anion layers shows that this difference is responsible for the two different BEDT-TTF packing motifs, as a consequence of weak H-bonding interactions between the terminal ethylene groups in the donor and the [M(C(2)O(4))(3)](3-) oxygen atoms.

Coaggregation of paramagnetic d- and f-block metal ions with a podand-framework amine phenol ligand.

This report covers initial studies in the coaggregation of nickel (Ni2+) and lanthanide (Ln3+) metal ions to form complexes with interesting structural and magnetic properties. The tripodal amine phenol ligand H3tam (1,1,1-tris(((2-hydroxybenzyl)amino)methyl)ethane) is shown to be particularly accommodating with respect to the geometric constraints of both transition and lanthanide metal ions, forming isolable complexes with both of these ion types. In the solid-state structure of [Ni(H2tam)(CH3CN)]PF6.2.5CH3CN.0.5CH3OH (1), the Ni(II) center has a distorted octahedral geometry, with an N3O2 donor set from the [H2tam]- ligand and a coordinated solvent (acetonitrile) occupying the sixth site. The reaction of stoichiometric amounts of H3tam with the Ni(II) ion in the presence of lanthanide(III) ions provides [LnNi2(tam)2]+ cationic complexes which contain coaggregated metal ions. These complexes are isolable and have been characterized by a variety of analytical techniques, with mass spectrometry proving to be particularly diagnostic. The solid-state structures of [LaNi2(tam)2(CH3OH)1/2(CH3CH2OH)1/2(H2O)]ClO4.0.5CH3OH.0.5CH3CH2OH.4H2O (2), [DyNi2(tam)2(CH3OH)(H2O)]ClO4.CH3OH. H2O(6), and [YbNi2(tam)2(H2O)]ClO4.2.58H2O(9) have been determined. Each complex contains two octahedral Ni(II) ions, each of which is encapsulated by the ligand tam3- in an N3O3 coordination sphere; each [Ni(tam)]-unit caps the lanthanide(III) ion via bridging phenoxy oxygen donor atoms. In 2, La3+ is eight-coordinated, while in 6, Dy(III) is seven- (to "weakly eight-") coordinated, and Yb(III) in 9 has a six-coordination environment. The complexes are symmetrically different, 2 possessing C2 symmetry and 6 and 9 having C1 symmetry. Magnetic studies of 2, 6, and 9 indicate that antiferromagnetic exchange coupling between the Ni(II) and Ln(III) ions increases with decreasing ionic radius of Ln(III).

An aqueous concentration model for riverine spills.

A numerical model is developed to predict the aqueous concentrations of sparingly soluble compounds resulting from oil, fuel, or chemical spills onto rivers. The model computes the concentration of compounds both in the slick phase and in the aqueous phase by simulating the processes that affect the fate of the spilled compound. Processes simulated by the model include spreading and drifting of the surface slick, evaporation from the slick, dissolution from the slick into the water, volatilization from the water, and longitudinal dispersion in the river. The model is used to simulate a hypothetical spill of jet fuel, demonstrating that the concentration of a compound in the aqueous phase is strongly linked to its concentration in the slick phase. The most soluble and most volatile compounds exhibit the highest aqueous concentrations in the early stages of the spill, but ultimately the less soluble and less volatile compounds reach the highest aqueous concentrations. Streamwise concentration gradients in the slick due to the rapid evaporation of the more volatile compounds are shown to have an effect on the aqueous concentration.

Processes controlling aqueous concentrations for riverine spills.

The aqueous concentrations of sparingly soluble compounds resulting from oil, fuel, or chemical spills onto rivers predicted by numerical spill models contain an inherent degree of uncertainty due to the inaccuracies, or bias, of the user supplied rate coefficients. Methods for estimating the values of spreading, evaporation, dissolution, volatilization, and longitudinal dispersion coefficients for a small sheltered river are reviewed, and the uncertainties associated with each coefficient are estimated. The uncertainties in the predicted aqueous concentrations are then computed using a concurrently developed riverine spill model for a simulated spill of 10,000 kg of jet fuel. The resulting aqueous concentrations were found to be most sensitive to the saturation concentrations and the dissolution rates, moderately sensitive to the evaporation rates and longitudinal dispersion coefficient, and nearly completely insensitive to the volatilization coefficient.

Molecular modelling and biological evaluation of a series of hydroxylated benzylideneanilines and benzylamines designed as tyrosine kinase inhibitors.

A series of hydroxylated benzylideneanilines and benzylamines were prepared and tested for inhibition of epidermal growth factor receptor-associated protein tyrosine kinase (PTK) activity in vitro. Molecular modelling and analysis of the biological results lead us to propose a minimal structural pharmacophore for two distinct binding sites within the PTK domain.