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Foster City, CA, United States

Gilead Sciences is an American biotechnology company that discovers, develops and commercializes therapeutics. For many years since the company was founded, the company concentrated primarily on antiviral drugs to treat patients infected with HIV, hepatitis B or influenza. In 2006, Gilead acquired two companies that were developing drugs to treat patients with pulmonary diseases. The company has fourteen commercially available products. Wikipedia.

Rulisek L.,Gilead Sciences
Journal of Physical Chemistry C | Year: 2013

The theoretical calculations of reduction potentials for the [M(H 2O)6]2+/3+, [M(NH3) 6]2+/3+, [M(en)3]2+/3+, [M(bipy)3]2+/3+, [M(CN)6]4-/3-, and [MCl6]4-/3- systems (M = Fe, Os, Ru) were carried out. The DFT(PBE)/def2-TZVP//DFT(PBE)/def2-SVP quantum chemical method was employed to obtain presumably accurate ionization energies, whereas the conductor-like screening model for real solvents (COSMO-RS) was selected as the most suitable method for calculations of solvation energies of the oxidized and reduced forms of the studied species. It has been shown that COSMO-RS may overcome problems related to directionality of hydrogen bonds in the second solvation sphere that previously led to errors of ∼1 V for the [Ru(H2O) 6]2+ complex employing PCM-like models. Thus, most of the values for (2+) → (3+) oxidations are now within 0.1-0.2 V from the experimental data, once the anticipated spin-orbit coupling effects in Os complexes (downshifting the calculated reduction potentials by ∼0.3 V) are taken into account. The robustness of the DFT(PBE)/COSMO-RS computational protocol is further verified by showing that reduction potentials obtained for selected 2+/3+ redox pairs with and without the inclusion of explicit second-sphere water molecules are almost identical. At the same time, it must be admitted that the calculated values of reduction potentials for systems involving quadruple charged species, exemplified here by [M(CN) 6]4-/3- and [MCl6]4-/3- redox pairs, might still not be within the grasp of contemporary solvation models, possibly due to the large values of solvation energies of their reduced (4-) forms that are in the range of 700-750 kcal mol-1 (30-33 eV) and possibly larger errors inherent in their calculations. Finally, a comparison is made with M06-L//SMD computational protocol, which is also shown to correct some of the deficiencies of previous PCM models. © 2013 American Chemical Society.

El-Bizri N.,Gilead Sciences
Channels (Austin, Tex.) | Year: 2011

The antianginal drug ranolazine exerts voltage- and use-dependent block (UDB) of several Na+ channel isoforms, including Na(v) 1.4. We hypothesized that ranolazine will similarly inhibit the paramyotonia congenita Na(v) 1.4 gain-of-function mutations, R1448C, R1448H, and R1448P that are associated with repetitive action potential firing. Whole-cell Na+ current (I(Na)) was recorded from HEK293 cells expressing the hNa(v) 1.4 WT or R1448 mutations. At a holding potential (HP) of -140 mV, ranolazine exerted UDB (10 Hz) of WT and R1448 mutations (IC 50 = 59 - 71 μM). The potency for ranolazine UDB increased when the frequency of stimulation was raised to 30 Hz (IC 50 = 20 - 27 uM). When the HP was changed to -70 mV to mimic the resting potential of an injured skeletal muscle fibre, the potency of ranolazine to block I(Na) further increased; values of ranolazine IC 50 for block of WT, R1448C, R1448H, and R1448P were 3.8, 0.9, 6.3, and 0.9 uM, respectively. Ranolazine (30 uM) also caused a hyperpolarizing shift in the voltage-dependence of inactivation of WT and R1448 mutations. The effects of ranolazine (30 uM) to reduce I(Na) were similar (~35% I(Na) inhibition) when different conditioning pulse durations (2-20 msec) were used. Ranolazine (10 μM) suppressed the abnormal I(Na) induced by slow voltage ramps for R1448C channels. In computer simulations, 3 μM ranolazine inhibited the sustained and excessive firing of skeletal muscle action potentials that are characteristic of myotonia. Taken together, the data indicate that ranolazine interacts with the open state and stabilizes the inactivated state(s) of Na(v)1.4 channels, causes voltage- and use-dependent block of I(Na) and suppresses persistent I(Na). These data further suggest that ranolazine might be useful to reduce the sustained action potential firing seen in paramyotonia congenita.

Hocek M.,Gilead Sciences | Fojta M.,Academy of Sciences of the Czech Republic
Chemical Society Reviews | Year: 2011

Basic aspects of DNA electrochemistry with a strong focus on the use of modified nucleobases as redox probes for electrochemical bioanalysis are reviewed. Intrinsic electrochemical properties of nucleobases in combination with artificial redox-active nucleobase modifications are frequently applied in this field. Synthetic approaches (both chemical and enzymatic) to base-modified nucleic acids are briefly summarized and their applications in redox labelling are discussed. Finally, analytical applications including DNA hybridization, primer extension, PCR, SNP typing, DNA damage and DNA-protein interaction analysis are presented (critical review, 91 references). © The Royal Society of Chemistry 2011.

The objectives of this cross-sectional, observational study were to determine the prevalence of self-reported headache among the employees of the large Swiss university hospital, to measure the impact of headache using the MIDAS questionnaire, to assess current treatment and to estimate economic burden of headache considering indirect costs. A self-administered questionnaire was distributed internally to 2000 randomly selected employees of the University Hospital Zurich. 1210 employees (60.5%) responded. Of the 1192 (98.5%) employees who provided sufficiently complete information, 723 (61%) reported at least one headache type in the last three months. The prevalence of migraine, and tension-type headache was 20% and 50%, respectively. Regarding the occupational groups, there was a trend that healthcare staff, administration employees, and medical technicians suffered more from headaches than physicians, correcting for age and sex. The economic consequences of lost productivity were calculated to amount to approximately 14 million Swiss Francs (9.5 million EUR), representing 3.2% of the overall annual expenditure of the hospital for personnel. Headache is highly prevalent among university hospital employees, with significant economic impact.

RuliSek L.,Gilead Sciences | Ryde U.,Lund University
Coordination Chemistry Reviews | Year: 2013

In this article, we review recent theoretical work that has complemented the extensive experimental data available for the multicopper oxidases (MCO) and led to the elucidation of the reaction mechanism of this class of enzymes. The MCOs couple four one-electron oxidations of substrates at the mononuclear type 1 copper (Cu-T1) site with the four-electron reduction of dioxygen at the trinuclear copper cluster (TNC). The TNC consists of three copper ions arranged in a unique triangular fashion. In its oxidised form and in some experimentally observed intermediates (the peroxy and native intermediates), this leads to a magnetic coupling of the unpaired electrons of the three copper ions, resulting in unusual spectroscopic features. By correlating experimental and theoretical data, an unambiguous mapping between the structural, energetic and spectroscopic properties of the various intermediates in the MCO reaction cycle can be established. In terms of theory, these studies involved quantum mechanics (QM; density-functional theory and multi-reference self-consistent field) calculations, combined QM and molecular mechanics (QM/MM) modelling, ranging from standard QM/MM optimisations to the combination of QM/MM optimisation with EXAFS spectroscopy and QM/MM free-energy perturbations to accurately address phenomena such as the Cu-T1 → TNC electron transfer, as well as the reduction potentials and acid constants of all the putative intermediates in the MCO reaction cycle. In summary, we try to demonstrate in this review that the MCOs are not only an attractive playground for theoretical methods, but the results of the calculations (when carefully correlated with and benchmarked against experimental data) can also be used to draw unambiguous conclusions about MCO structure and reactivity. © 2012 Elsevier B.V..

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