Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function

The HYDE scoring function consistently describes hydrogen bonding, the hydrophobic effect and desolvation. It relies on HYdration and DEsolvation terms which are calibrated using octanol/water partition coefficients of small molecules. We do not use affinity data for calibration, therefore HYDE is generally applicable to all protein targets. HYDE reflects the Gibbs free energy of binding while only considering the essential interactions of protein-ligand complexes. The greatest benefit of HYDE is that it yields a very intuitive atom-based score, which can be mapped onto the ligand and protein atoms. This allows the direct visualization of the score and consequently facilitates analysis of protein-ligand complexes during the lead optimization process. In this study, we validated our new scoring function by applying it in large-scale docking experiments. We could successfully predict the correct binding mode in 93% of complexes in redocking calculations on the Astex diverse set, while our performance in virtual screening experiments using the DUD dataset showed significant enrichment values with a mean AUC of 0.77 across all protein targets with little or no structural defects. As part of these studies, we also carried out a very detailed analysis of the data that revealed interesting pitfalls, which we highlight here and which should be addressed in future benchmark datasets.     

Syntheses and PE-Spectroscopic Investigations of 2,6- and 3,5-Bridged 1,4-Dimethylidenecyclohexanes

Three 1,4-dimethylidenecyclohexanes, bridged in the 2,6- and 3,5-positions by two ethano ( 4 ), one ethano and one propano ( 5 ), and two propano bridges ( 6 ) have been synthesized. The interaction of the two exocyclic methylidene groups has been investigated by He(I) photoelectron (PE) spectroscopy. It revealed a slightly larger energy difference (0.8 eV) for 4 and 5 as compared to the parent 1,4-dimethylidenecyclohexane ( 7 ) (0.7 eV). The interpretation of the PE spectra was based on the comparison with PE data of related systems and with the results of semiempirical calculations on 4–6 .     

Fluorescence-based active site probes for profiling deubiquitinating enzymes

Novel ubiquitin-based active site probes including a fluorescent tag have been developed and evaluated. A new, functionalizable electrophilic trap is utilized allowing for late stage diversification of the probe. Attachment of fluorescent dyes allowed direct detection of endogenous deubiquitinating enzyme (DUB) activities in cell extracts by in-gel fluorescence imaging.     

Rearrangement from the heteroantiaromatic borole to the heteroaromatic azaborine motif

Treatment of 9-chloro-9-borafluorene with N,O-bis(trimethylsilyl)hydroxylamine results in 10-trimethylsilyloxy-9-aza-10-boraphenanthrene 6b. NMR spectroscopy shows that the expected antiaromatic 9-(trimethylsilyloxyamino)-9-borafluorene 5b rearranges to the formally aromatic phenanthrene 6b at room temperature.     

Borylene transfer from an iron bis(borylene) complex: synthesis of 1,4-diboracyclohexadiene and 1,4-dibora-1,3-butadiene complexes

Diene to be made: By tuning the size of acetylenic substituents, 1,4-diboracyclohexadiene and unprecedented 1,4-dibora-1,3-butadiene complexes were generated in a controlled manner by borylene transfer from an iron bis(borylene) complex to alkynes (see scheme).     

Rhodium-Mediated Stoichiometric Synthesis of Mono-, Bi-, and Bis-1,2-Azaborinines: 1-Rhoda-3,2-azaboroles as Reactive Precursors

A series of highly substituted 1,2-azaborinines, including a phenylene-bridged bis-1,2-azaborinine, was synthesized from the reaction of 1,2-azaborete rhodium complexes with variously substituted alkynes. 1-Rhoda-3,2-azaborole complexes, which are accessible by phosphine addition to the corresponding 1,2-azaborete complexes, were also found to be suitable precursors for the synthesis of 1,2-azaborinines and readily reacted with alkynyl-substituted 1,2-azaborinines to generate new regioisomers of bi-1,2-azaborinines, which feature directly connected aromatic rings. Their molecular structures, which can be viewed as boron-nitrogen isosteres of biphenyls, show nearly perpendicular 1,2-azaborinine rings. The new method using rhodacycles instead of 1,2-azaborete complexes as precursors is shown to be more effective, allowing the synthesis of a wider range of 1,2-azaborinines.     

Comparison of Oxidative Aromatic Coupling and the Scholl Reaction

Does the dehydrogenative coupling of aromatic compounds mediated by AlCl₃ at high temperatures and also by FeCl₃, MoCl₅, PIFA, or K₃[Fe(CN)₆] at room temperature proceed by the same mechanism in all cases? With the growing importance of the synthesis of aromatic compounds by double C? H activation to give various biaryl structures, this question becomes pressing. Since some of these reactions proceed only in the presence of non‐oxidizing Lewis acids and some only in the presence of certain oxidants, the authors venture the hypothesis that, depending on the electronic structure of the substrates and the nature of the “catalyst”, two different mechanisms can operate. One involves the intermediacy of a radical cation and the other the formation of a sigma complex between the acid and the substrate. The goal of this Review is to encourage further mechanistic studies hopefully leading to an in‐depth understanding of this phenomenon.     

Discovery of Potential,Dual-Active Histamine H3 Receptor Ligands with Combined Antioxidant Properties

In an attempt to find new dual acting histamine H₃ receptor (H₃R) ligands, we designed a series of compounds, structurally based on previously described in our group, a highly active and selective human histamine H₃ receptor (hH₃R) ligand KSK63. As a result, 15 obtained compounds show moderate hH₃R affinity, the best being the compound 17 (hH₃R K_i = 518 nM). Docking to the histamine H₃R homology model revealed two possible binding modes, with key interactions retained in both cases. In an attempt to find possible dual acting ligands, selected compounds were tested for antioxidant properties. Compound 16 (hH₃R K_i = 592 nM) showed the strongest antioxidant properties at the concentration of 10⁻⁴ mol/L. It significantly reduced the amount of free radicals presenting 50–60% of ascorbic acid activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, as well as showed antioxidative properties in the ferric reducing antioxidant power (FRAP) assay. Despite the yet unknown antioxidation mechanism and moderate hH₃R affinity, 16 (QD13) constitutes a starting point for the search of potential dual acting H₃R ligands-promising tools for the treatment of neurological disorders associated with increased neuronal oxidative stress.     

Soluble oligoaramide precursors--a novel class of building blocks for rod-coil architectures

A new synthetic route is described that allows the reversible conversion of the inherently insoluble oligo-p-benzamides into soluble materials through the formation of imidoyl chlorides. Syntheses of the corresponding dimer, trimer, and tetramer are reported; these compounds can easily be purified by crystallization and are accessible on the multigram scale. Structural proof was obtained by single-crystal X-ray structures of the trimer and tetramer precursors. They can be selectively functionalized into amides or esters at the terminal carboxylic acid group followed by hydrolysis of the imidoyl chlorides to the parent amides. This new class of compounds gives access to strongly aggregating rigid rodlike materials in few synthetic steps, as is demonstrated by the preparation of poly(ethylene glycol)-co-oligo(p-benzamide) rod-coil block copolymers.