A QSAR model for the prediction of CNS activity was developed and validated based on data from an in‐house database of “drug‐like” compounds. The model has demonstrated its applicability for novel chemical structures and its usefulness for the design of CNS‐focused compound libraries.
The dynamic behavior of insulin in solution and its binding geometry with the insulin receptor (IR) have been the focus of experimental and computational studies. We investigated how the structure of an orally deliverable insulin changes in solution after vitamin B12 conjugation and its effect on IR binding capacity. In vitro immunoelectron microscopy confirms conjugate activity, IR binding, and cellular uptake.
Anchors aweigh! The synthesis of tryptophan–amphotericin B conjugates (see figure) is described. The membrane‐anchoring effect of tryptophane was thus combined with the pore‐formation effect of amphotericin B leading to high channel activity in sterol‐free liposomes.
See you later amyloid β : A screen of a small library of oxime oligomers with an HTS fluorescence assay for amyloid fibril inhibition and subsequent investigation by atomic force microscopy revealed two new micromolar inhibitors of amyloid fibril formation. These new inhibitors have IC50 values in the 10 μM range.
More than the sum of its parts : The seeds of Nigella sativa have been a traditional herbal remedy for ailments such as asthma, diarrhea, and cancer. Their essential oil is rich in polyunsaturated fatty acids and thymoquinone. By linking them covalently, a tremendous boost in anticancer activity can be achieved in resistant tumor cells.
Catch a tiger by the tail : We have demonstrated that by feeding nonmotile mutant C. jejuni bacteria with a neutral azide‐labelled pseudaminic acid precursor we can restore their ability to generate functional flagella. The presence of azido‐pseudaminic acid on the surface of the flagella provides a bio‐orthogonal chemical handle that can be used to modify the flagellar proteins.
Assemble & chelate : Click chemistry enables the efficient and selective synthesis of structurally diverse conjugates containing a central di‐1,2,3‐triazole chelator for complexation with [99mTc(CO)3]+. Use of appropriate building blocks allows the modulation of pharmacological relevant characteristics of the conjugate, or the introduction of secondary probes suitable for imaging modalities other than single photon emission computed tomography (SPECT).
Uranyl ion‐specific DNAzyme : A DNAzyme (lower strand) cleaves the substrate (upper strand) in the presence of the uranyl ion. The enzyme folds into a bulged three‐way‐junction structure with catalytically important nucleotides residing in the bulge. A highly conserved G?A mismatch is also crucial for the enzyme's activity.
Choosing the right compounds to synthesise from large virtual combinatorial libraries is a current challenge for the pharmaceutical industry. Herein we describe a highly optimised method that aligns lead‐like properties with compound diversity. The methods are illustrated by considering a two‐dimensional library based on the interesting spirocyclic bis‐azetidine template.
Through construction of an iminosugar library and in situ cell‐based screening, several iminosugar compounds with the ability to stimulate IFN‐γ secretion in vitro were discovered. Among these compounds, one was able to strongly induce IFN‐γ secretion and showed remarkable antibacterial effects in vivo.
It's raining, it's porin : Fragment ligation of OmpF ion channels was achieved by using the split Psp‐GBD Pol intein; this allowed reconstitution of active trimeric porin. In combination with cysteine modification at an internal position, the porin's conductance properties were altered.
Playing polo : Small‐molecule inhibitors of polo‐like kinase 1 are mostly ATP‐competitive, and thus face enormous specificity hurdles. This communication explores the concept of inhibiting Plk1 with a small‐molecule inhibitor of the protein–protein interactions required for Plk1 function.
What parameters determine promiscuity? A compound's potential for promiscuity (pharmacological activity at multiple targets) may be influenced by molecular parameters such as ionization state, lipophilicity, and molecular weight. In an analysis of recent Roche compounds we found that a positive charge is an important determinant for potential promiscuity; aminergic activity was found to be the main reason for overt promiscuity.
Magic Mn–salen metallozyme : The design of an original, artificial, inorganic, complex‐protein adduct, has led to a better understanding of the synergistic effects of both partners. The exclusive formation of sulfoxides by the hybrid biocatalyst, as opposed to sulfone in the case of the free inorganic complex, highlights the modulating role of the inorganic‐complex‐binding site in the protein.
Ancillary oxygenase : OxyE is identified as a likely ancillary C‐4 hydroxylase used during oxytetracycline biosynthesis in Streptomyces rimosus. The synergistic actions of oxygenases OxyE and OxyL ensure complete oxidative tailoring and prevent irreversible shunt modifications of the biosynthetic intermediate.
Fragment formal concept analysis (FragFCA) for compound classification: Signature fragment combinations for compound classes with closely related biological activity were identified using FragFCA. These combinations are used to accurately classify active test compounds on the basis of fragment mapping. FragFCA can extract class‐specific fragment combinations from compounds active against different target families that have signature character and practical utility in compound classification and database searching.
Bright field image of a unipolar fatigued Bi0.5Na0.5TiO3‐6BaTiO3 lead‐free ceramic. See Feature Article, “Electric Fatigue of Lead‐free Piezoelectric Materials,” by Julia Glaum and Mark Hoffman. Micrograph courtesy of Dr. Ljubomira Ana Schmitt from the Institute of Materials Science, Technische Universität Darmstadt, Germany.
Coculture control : We report a combined photochemical and electroactive self‐assembled monolayer (SAM)‐based substrate strategy to generate a coculture platform with spatial and temporal control of cell–cell interactions. These dynamic substrates can present a variety of ligands on the surface for biospecific interactions between the ligands and cell surface receptors. Photopatterning enables the ligands to be immobilized in patterns and even gradients.
Metal‐based antitumor agents : Halogen‐substituted titanium salane complexes showed IC50 values comparable to cisplatin. In contrast to their alkyl‐substituted congeners, they almost exclusively induced apoptotic cell death. This unique combination of very low IC50 values and pronounced preference for apoptosis makes them promising therapeutic agents.
Probing SAR : The 1‐(biphenyl‐4‐ylmethyl)‐1H‐benzo[d]imidazole moiety is known to be an essential structural component of telmisartan for PPARγ activation. This study focused on the substituents at position 2 of the benzimidazole in an attempt to optimize PPARγ activation. In particular, the elongation of the alkyl chain and the introduction of an aromatic ring system were studied (shown).
