A repetitive one-step method for oligoarene synthesis using catalyst-controlled chemoselective cross-coupling

A method for oligoarene synthesis involving chemoselective cross-coupling as the key reaction was developed. Boronic acids with a chloro or trifluoromethanesulfonyloxy group were used as the monomer precursors with either of two chemoselective catalytic systems: Pd with P(t-Bu)(3), and Pd with 1,1'-bis(diphenylphosphino)ferrocene (DPPF). This method enabled elongation by one benzene unit in every step and thus reduced the number of steps required for elongation of oligoarene chains with well-defined lengths and sequences of substituted benzene rings.     

A data mining method to facilitate SAR transfer

A challenging practical problem in medicinal chemistry is the transfer of SAR information from one chemical series to another. Currently, there are no computational methods available to rationalize or support this process. Herein, we present a data mining approach that enables the identification of alternative analog series with different core structures, corresponding substitution patterns, and comparable potency progression. Scaffolds can be exchanged between these series and new analogs suggested that incorporate preferred R-groups. The methodology can be applied to search for alternative analog series if one series is known or, alternatively, to systematically assess SAR transfer potential in compound databases.     

REPROVIS-DB: a benchmark system for ligand-based virtual screening derived from reproducible prospective applications

Benchmark calculations are essential for the evaluation of virtual screening (VS) methods. Typically, classes of known active compounds taken from the medicinal chemistry literature are divided into reference molecules (search templates) and potential hits that are added to background databases assumed to consist of compounds not sharing this activity. Then VS calculations are carried out, and the recall of known active compounds is determined. However, conventional benchmarking is affected by a number of problems that reduce its value for method evaluation. In addition to often insufficient statistical validation and the lack of generally accepted evaluation standards, the artificial nature of typical benchmark settings is often criticized. Retrospective benchmark calculations generally overestimate the potential of VS methods and do not scale with their performance in prospective applications. In order to provide additional opportunities for benchmarking that more closely resemble practical VS conditions, we have designed a publicly available compound database (DB) of reproducible virtual screens (REPROVIS-DB) that organizes information from successful ligand-based VS applications including reference compounds, screening databases, compound selection criteria, and experimentally confirmed hits. Using the currently available 25 hand-selected compound data sets, one can attempt to reproduce successful virtual screens with other than the originally applied methods and assess their potential for practical applications.     

Study of Tamiflu sensitivity to variants of A/H5N1 virus using different force fields

An accurate estimation of binding free energy of a ligand to receptor ΔG(bind) is one of the most important problems in drug design. The success of solution of this problem is expected to depend on force fields used for modeling a ligand-receptor complex. In this paper, we consider the impact of four main force fields, AMBER99SB, CHARMM27, GROMOS96 43a1, and OPLS-AA/L, on the binding affinity of Oseltamivir carboxylate to the wild-type and Y252H, N294S, and H274Y mutants of glycoprotein neuraminidase from the pandemic A/H5N1 virus. Having used the molecular mechanic-Poisson-Boltzmann surface area method, we have shown that ΔG(bind), obtained by AMBER99SB, OPLS-AA/L, and CHARMM27, shows the high correlation with the available experimental data. They correctly capture the binding ranking Y252H → WT → N294S → H274Y observed in experiments (Collins, P. J. et al. Nature 2008, 453, 1258). In terms of absolute values of binding scores, results obtained by AMBER99SB are in the nearest range with experiments, while OPLS-AA/L, which is applied to study binding of Oseltamivir to the influenza virus for the first time, gives rather big negative values for ΔG(bind). GROMOS96 43a1 provides a lower correlation as it supports Oseltamivir to be more resistant to N294S than H274Y. Our study suggests that force fields have pronounced influence on theoretical estimations of binding free energy of a ligand to receptor. The effect of all-atom models on dynamics of the binding pocket as well as on the hydrogen-bond network between Oseltamivir and receptors is studied in detail. The hydrogen network, obtained by GROMOS, is weakest among four studied force fields.     

Recurrent points and non-wandering points of graph maps

Let G be a graph and f:G→G be a continuous map. Denote by P(f), R(f) and Ω(f) the sets of periodic points, recurrent points and non-wandering points of f, respectively. In this paper we show that: (1) If L=(x,y) is an open arc contained in an edge of G such that {fm(x),fk(y)}⊂(x,y) for some m,k∈N, then R(f)∩(x,y)≠∅; (2) Any isolated point of P(f) is also an isolated point of Ω(f); (3) If x∈Ω(f)−Ω(fn) for some n∈N, then x is an eventually periodic point. These generalize the corresponding results in W. Huang and X. Ye (2001) [9] and J. Xiong (1983, 1986) [17] and [19] on interval maps or tree maps.     

Numerical approximation for a Baer-Nunziato model of two-phase flows

We present a well-balanced numerical scheme for approximating the solution of the Baer-Nunziato model of two-phase flows by balancing the source terms and discretizing the compaction dynamics equation. First, the system is transformed into a new one of three subsystems: the first subsystem consists of the balance laws in the gas phase, the second subsystem consists of the conservation law of the mass in the solid phase and the conservation law of the momentum of the mixture, and the compaction dynamic equation is considered as the third subsystem. In the first subsystem, stationary waves are used to build up a well-balanced scheme which can capture equilibrium states. The second subsystem is of conservative form and thus can be numerically treated in a standard way. For the third subsystem, the fact that the solid velocity is constant across the solid contact suggests us to compose the technique of the Engquist-Osher scheme. We show that our scheme is capable of capturing exactly equilibrium states. Moreover, numerical tests show the convergence of approximate solutions to the exact solution.     

Highly sensitive phototransistor with crystalline microribbons from new π-extended pyrene derivative via solution-phase self-assembly

A new pyrene-cored π-conjugated molecule has been synthesized through Sonogashira coupling reaction. The single-crystalline microribbon-based FET exhibited the highest mobility of 0.7 cm(2) V(-1) s(-1) (I(on)/I(off) > 10(6)). Single-crystalline microribbons were employed to operate in an organic phototransistor (OPT) under very low light intensity (I = 5.6 μW cm(-2)).     

Effects of all-atom force fields on amyloid oligomerization: replica exchange molecular dynamics simulations of the Aβ(16-22) dimer and trimer

The aim of this work is to investigate the effects of molecular mechanics force fields on amyloid peptide assembly. To this end, we performed extensive replica exchange molecular dynamics (REMD) simulations on the monomer, dimer and trimer of the seven-residue fragment of the Alzheimer's amyloid-β peptide, Aβ(16-22), using the AMBER99, GROMOS96 and OPLS force fields. We compared the force fields by analysing the resulting global and local structures as well as the free energy landscapes at 300 K. We show that AMBER99 strongly favors helical structures for the monomer and does not predict any β-sheet structure for the dimer and trimer. In contrast, the dimer and trimer modeled by GROMOS96 form antiparallel β-sheet structures, while OPLS predicts diverse structures. Overall, the free energy landscapes obtained by three force fields are very different, and we also note a weak structural dependence of our results on temperature. The implications of this computational study on amyloid oligomerization, fibril growth and inhibition are also discussed.     

Interspecies comparison of chemical composition and anxiolytic-like effects of lavender oils upon inhalation

Essential oils have traditionally been used for decades to alleviate the symptoms of various mental problems. In terms of anxiolytic-like properties, lavender oil is probably the most commonly used and best-studied essential oil. Although there is compositional variance among the oils extracted from different origins, there have been few studies performed to date to investigate how these differences affect the expression of anxiolytic-like activity. This paper discusses the interspecies differences and contributions of the main constituents in the expression of anxiolytic-like effects upon inhalation, as assessed in mice by the elevated-plus maze test, by comparing the essential oils from six different species of Lavandula. The results showed qualitative and quantitative variations in the tested oils, which results in significant differences in their anxiolytic-like activities. Our findings also suggest that linalyl acetate (LA) works synergistically with linalool (LO) and that the presence of both LA and LO is essential for the whole oil to work as an inhaled anti-anxiety agent.     

On a multistage discrete stochastic optimization problem with stochastic constraints and nested sampling

Mathematical Programming -