Bilayered micelles, or bicelles, which consist of a mixture of long- and short-chain phospholipids, are a popular model membrane system. Depending on composition, concentration, and temperature, bicelle mixtures may adopt an isotropic phase or form an aligned phase in magnetic fields. Well-resolved (1)H NMR spectra are observed in the isotropic or so-called fast-tumbling bicelle phase, over the range of temperatures investigated (10-40 degrees C), for molar ratios of long-chain lipid to short-chain lipid between 0.20 and 1.0. Small angle neutron scattering data of this phase are consistent with the model in which bicelles were proposed to be disk-shaped. The experimentally determined dimensions are roughly consistent with the predictions of R.R. Vold and R.S. Prosser (J. Magn. Reson. B 113 (1996)). Differential paramagnetic shifts of head group resonances of dimyristoylphosphatidylcholine (DMPC) and dihexanoylphosphatidylcholine (DHPC), induced by the addition of Eu(3+), are also consistent with the bicelle model in which DHPC is believed to be primarily sequestered to bicelle rims. Selective irradiation of the DHPC aliphatic methyl resonances results in no detectable magnetization transfer to the corresponding DMPC methyl resonances (and vice versa) in bicelles, which also suggests that DHPC and DMPC are largely sequestered in the bicelle. Finally, (1)H spectra of the antibacterial peptide indolicidin (ILPWKWPWWPWRR-NH(2)) are compared, in a DPC micellar phase and the above fast-tumbling bicellar phases for a variety of compositions. The spectra exhibit adequate resolution and improved dispersion of amide and aromatic resonances in certain bicelle mixtures.
The complex nature of multifactorial diseases, such as
Morbus Alzheimer,
has produced a strong need to design multitarget-directed ligands
to address the involved complementary pathways. We performed a purposive
structural modification of a tetratarget small-molecule, that is contilisant,
and generated a combinatorial library of 28 substituted chromen-4-ones.
The compounds comprise a basic moiety which is linker-connected to
the 6-position of the heterocyclic chromenone core. The syntheses
were accomplished by Mitsunobu- or Williamson-type ether formations.
The resulting library members were evaluated at a panel of seven human
enzymes, all of which being involved in the pathophysiology of neurodegeneration.
A concomitant inhibition of human acetylcholinesterase and human monoamine
oxidase B, with IC50 values of 5.58 and 7.20 μM,
respectively, was achieved with the dual-target 6-(4-(piperidin-1-yl)butoxy)-4H-chromen-4-one (7).
Today, most pharmaceutical companies complement their traditional R&D models with some variation on the Open Innovation (OI) approach in an effort to better access global scientific talent, ideas and hypotheses. Traditional performance indicators that measure economic returns from R&D through commercialization are often not applicable to the practical assessment of these OI approaches, particularly within the context of early drug discovery. This leaves OI programs focused on early R&D without a standard assessment framework from which to evaluate overall performance. This paper proposes a practical dashboard for such assessment, encompassing quantitative and qualitative elements, to enable decision-making and improvement of future performance. The use of this dashboard is illustrated using real-time data from the Lilly Open Innovation Drug Discovery (OIDD) program.
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