Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity

Thrombosis is a life-threatening disease with a high mortality rate in many countries. Even though anti-thrombotic drugs are available, their serious side effects compel the search for safer drugs. In search of a safer anti-thrombotic drug, Quantitative Structure-Activity Relationship (QSAR) could be useful to identify crucial pharmacophoric features. The present work is based on a larger data set comprising 1121 diverse compounds to develop a QSAR model having a balance of acceptable predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The developed six parametric model fulfils the recommended values for internal and external validation along with Y-randomization parameters such as R2tr = 0.831, Q2LMO = 0.828, R2ex = 0.783. The present analysis reveals that anti-thrombotic activity is found to be correlated with concealed structural traits such as positively charged ring carbon atoms, specific combination of aromatic Nitrogen and sp2-hybridized carbon atoms, etc. Thus, the model captured reported as well as novel pharmacophoric features. The results of QSAR analysis are further vindicated by reported crystal structures of compounds with factor Xa. The analysis led to the identification of useful novel pharmacophoric features, which could be used for future optimization of lead compounds.

A lysine ring in HIV capsid pores coordinates IP6 to drive mature capsid assembly

The HIV capsid self-assembles a protective conical shell that simultaneously prevents host sensing whilst permitting the import of nucleotides to drive DNA synthesis. This is accomplished through the construction of dynamic, highly charged pores at the centre of each capsid multimer. The clustering of charges required for dNTP import is strongly destabilising and it is proposed that HIV uses the metabolite IP6 to coordinate the pore during assembly. Here we have investigated the role of inositol phosphates in coordinating a ring of positively charged lysine residues (K25) that forms at the base of the capsid pore. We show that whilst IP5, which can functionally replace IP6, engages an arginine ring (R18) at the top of the pore, the lysine ring simultaneously binds a second IP5 molecule. Dose dependent removal of K25 from the pore severely inhibits HIV infection and concomitantly prevents DNA synthesis. Cryo-tomography reveals that K25A virions have a severe assembly defect that inhibits the formation of mature capsid cones. Monitoring both the kinetics and morphology of capsids assembled in vitro reveals that while mutation K25A can still form tubes, the ability of IP6 to drive assembly of capsid cones has been lost. Finally, in single molecule TIRF microscopy experiments, capsid lattices in permeabilised K25 mutant virions are rapidly lost and cannot be stabilised by IP6. These results suggest that the coordination of IP6 by a second charged ring in mature hexamers drives the assembly of conical capsids capable of reverse transcription and infection.

Investigating the effects of the planetary rings on the azimuthal magnetic field at Saturn

<p>Magnetic field observations from the 22 Cassini Grand Finale orbits have shown a mean lagging azimuthal magnetic field configuration on magnetic field lines mapping from Saturn to its main rings in the equatorial plane, with some orbit to orbit variability. A prominent feature is observed in the southern hemisphere on field lines connecting to the B-ring on 70% of the orbits, which is spatially consistent with the location of in-falling dust indicated by the Cosmic Dust Analyser instrument. In our work, we examine the possible connection between the in-falling charged dust and the B-ring magnetic field feature. We also use a simple steady-state model to couple the planetary ionosphere to a weakly conducting ring ionosphere over the main rings, where the model output shows an expected leading field configuration associated with the rings. The discrepancy between the simple theoretical model and the data indicates the presence of additional processes (e.g. departure from Keplerian velocity of the charged ring particles), which will be discussed. We will further discuss the likely connection between the observed lagging field configuration in the middle magnetosphere and in the inner magnetosphere.  </p>

Fabrication and Characterization of Electrospun Aligned Porous PAN/Graphene Composite Nanofibers

A modified parallel electrode method (MPEM), conducted by placing a positively charged ring between the needle and the paralleled electrode collector, was presented to fabricate aligned polyacrylonitrile/graphene (PAN/Gr) composite nanofibers (CNFs) with nanopores in an electrospinning progress. Two kinds of solvents and one kind of nanoparticle were used to generate pores on composite nanofibers. The spinning parameters, such as the concentration of solute and solvent, spinning voltage and spinning distance were discussed, and the optimal parameters were determined. Characterizations of the aligned CNFs with nanopores were investigated by scanning electron microscopy (SEM), fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD) analysis, transmission electron microscopy (TEM), high-resistance meter, and other methods. The results showed that graphene (Gr) nanoparticles were successfully introduced into aligned CNFs with nanopores and almost aligned along the axis of the CNFs. The MPEM method could make hydrophobic materials more hydrophobic, and improve the alignment degree and conductive properties of electrospun-aligned CNFs with nanopores. Moreover, the carbonized CNFs with nanopores, used as an electrode material, had a smaller charge-transfer resistance, suggesting potential application in electrochemical areas and electron devices.