Design of multi-binding-site inhibitors, ligand efficiency, and consensus screening of avian influenza H5N1 wild-type neuraminidase and of the oseltamivir-resistant H274Y variant

The binding sites of wild-type avian influenza A H5N1 neuraminidase, as well as those of the Tamiflu (oseltamivir)-resistant H274Y variant, were explored computationally to design inhibitors that target simultaneously several adjacent binding sites of the open conformation of the virus protein. The compounds with the best computed free energies of binding, in agreement by two docking methods, consensus scoring, and ligand efficiency values, suggest that mimicking a polysaccharide, beta-lactam, and other structures, including known drugs, could be routes for multibinding site inhibitor design. This new virtual screening method based on consensus scoring and ligand efficiency indices is introduced, which allows the combination of pharmacodynamic and pharmacokinetic properties into unique measures.     

Regioselectivity in azahydro[60]fullerene derivatives: application of general-purpose reactivity indicators

To attempt theoretical predictions of the regioselectivity pattern in molecules with multiple reactive sites, the energies of formation of all possible isomers are usually considered. This means that the computing becomes highly demanding if high theoretical levels are used. The study objective was to predict the regioselectivity in the reaction of hydrogen addition onto azahydro[60]fullerene C 59H n+1 N ( n = 0-4) systems using a new reactivity indicator termed general-purpose reactivity indicator, Xi Delta N相似文献   

High resolution atomic coherent control via spectral phase manipulation of an optical frequency comb

We demonstrate high resolution coherent control of cold atomic rubidium utilizing spectral phase manipulation of a femtosecond optical frequency comb. Transient coherent accumulation is directly manifested by the enhancement of signal amplitude and spectral resolution via the pulse number. The combination of frequency comb technology and spectral phase manipulation enables coherent control techniques to enter a new regime with natural linewidth resolution.     

Global dominated splittings and the Newhouse phenomenon

We prove that given a compact -dimensional boundaryless manifold , , there exists a residual subset of the space of diffeomorphisms such that given any chain-transitive set of , then either admits a dominated splitting or else is contained in the closure of an infinite number of periodic sinks/sources. This result generalizes the generic dichotomy for homoclinic classes given by Bonatti, Diaz, and Pujals (2003).

It follows from the above result that given a -generic diffeomorphism , then either the nonwandering set may be decomposed into a finite number of pairwise disjoint compact sets each of which admits a dominated splitting, or else exhibits infinitely many periodic sinks/sources (the `` Newhouse phenomenon"). This result answers a question of Bonatti, Diaz, and Pujals and generalizes the generic dichotomy for surface diffeomorphisms given by Mañé (1982).

     

Dye-sensitized photooxygenation of sugar-furans as synthetic strategy for novel C-nucleosides and functionalized exo-glycals

The methylene blue-sensitized photooxygenation of β-ribofuranosyl furan 1e followed by in situ Et₂S treatment afforded the conformationally stable β-ribofuranoside 4e almost quantitatively. The latter was converted to pyridazine C-nucleoside 6e by cyclization with NH₂NH₂ and to pyrazoline 7e through a 1,3-dipolar cycloaddition with diazomethane. Attempts to epoxidize the double bond failed both by dimethyldioxirane (DMDO), which left 4e unchanged, and by NEt₃/t-BuOOH or NaOO-t-Bu which respectively afforded the new and unexpected exo-glycals E,Z-8e and the novel furan derivative 9.     

Interfacial water on Cl- and H-terminated Si(111) surfaces from first-principles calculations

The properties of interfacial water on Cl- and H-terminated Si(111) surfaces are investigated using a first-principles approach and characterized by means of energetic analysis combined with hydrogen-bond counting. The interaction of water with both substrates is found to be significantly weak, although bonding with the Cl-terminated Si(111) surface is relatively stronger because of the electrostatic contribution. According to a molecular picture for attributing the hydrophilic/hydrophobic character, both surfaces should be considered hydrophobic, at variance with the interpretation of recent ultrafast electron crystallography experiments, which seems instead to support a hydrophilic nature of the Cl-terminated Si(111) substrate.     

Open computing grid for molecular science and engineering

Grid is an emerging infrastructure for distributed computing that provides secure and scalable mechanisms for discovering and accessing remote software and data resources. Applications built on this infrastructure have great potential for addressing and solving large scale chemical, pharmaceutical, and material science problems. The article describes the concept behind grid computing and will present the OpenMolGRID system that is an open computing grid for molecular science and engineering. This system provides grid enabled components, such as a data warehouse for chemical data, software for building QSPR/QSAR models, and molecular engineering tools for generating compounds with predefined chemical properties or biological activities. The article also provides an overview about the availability of chemical applications in the grid.     

DFT Calculations and Synthesis Reveal: Key Intermediates,Omitted Mechanisms,and Unsymmetrical Bimane Products

Theoretical and experimental mixed approaches are complementary and valuable. Our DFT calculations support the mechanism suggested by Kosower, adding to it a key diaziridine intermediate that determines the relative product distribution of this reaction. Our results are consistent with the formation of the diazoketene intermediate as the rate-limiting step. Based on curve fittings, first or second-order kinetics cannot be ruled out. This may indicate that more than one mechanism is simultaneously at play in this transformation. This unexpected outcome led us to study an alternative cyclopropenone intermediate. Although cyclopropenone is not likely to be formed under thermal conditions, adding it to the reaction mixture results in bimane structures. The most staggering finding from this investigation was the unanticipated generation of the unsymmetrical anti-(Me,Me)(Ph,Ph)bimane. The optimization of this route towards unsymmetrical bimanes will require additional investigation.