Comparison of virtual high-throughput screening methods for the identification of phosphodiesterase-5 inhibitors

Reliable and effective virtual high-throughput screening (vHTS) methods are desperately needed to minimize the expenses involved in drug discovery projects. Here, we present an improvement to the negative image-based (NIB) screening: the shape, the electrostatics, and the solvation state of the target protein's ligand-binding site are included into the vHTS. Additionally, the initial vHTS results are postprocessed with molecular mechanics/generalized Born surface area (MMGBSA) calculations to estimate the favorability of ligand-protein interactions. The results show that docking produces very good early enrichment for phosphodiesterase-5 (PDE-5); however, in general, the NIB and the ligand-based screening performed better with or without the added electrostatics. Furthermore, the postprocessing of the NIB screening results using MMGBSA calculations improved the early enrichment for the PDE-5 considerably, thus, making hit discovery affordable.     

Carbohydrates electrocatalytic oxidation using CNT-NiCo-oxide modified electrodes

A new sensor for an amplified electrochemical detection of carbohydrates is proposed, where carbohydrates are oxidized by CNT-NiCo-oxide composite in basic solutions. Cyclic voltammograms of the modified electrode show a stable and well defined redox couple in alkaline media due to the synergy of Ni(II)/Ni(III) system with Co(II)/Co(III). The modified electrode shows excellent electrocatalytic activity towards monosaccharides oxidation at reduced overpotential in alkaline solutions. Six monosaccharides were determined amperometrically at the surface of this modified electrode with high sensitivity over a wide range of concentrations, from 0.02 up to 12.12 mM. Low detection limit of 5 μM for glucose could be obtained.     

Quantitative liver iron measurement by magnetic resonance imaging: in vitro and in vivo assessment of the liver to muscle signal intensity and the R2* methods

Purpose

To evaluate the liver-to-muscle signal intensity and R2* methods to gain a transferable, clinical application for liver iron measurement.

Materials and Methods

Sixteen liver phantoms and 33 human subjects were examined using three 1.5-T MRI scanners from two different vendors. Phantom-to-muscle and liver-to-muscle signal intensity ratios were analyzed to determine MRI estimated phantom and hepatic iron concentration (M-PIC and M-HIC, respectively). R2* was calculated for the phantoms and the liver of human subjects. Seven patients' biochemical hepatic iron concentration was obtained.

Results

M-PIC and R2* results of three scanners correlated linearly to phantom iron concentrations (r=0.984 to 0.989 and r=0.972 to 0.981, respectively), and no significant difference between the scanners was found (P=.482 and P=.846, respectively) in vitro. The patients' R2* correlated linearly to M-HIC of the standard scanner (r=0.981). M-HIC values did not differ from those obtained from the biopsy specimens (P=.230). The difference in M-HIC was significant, but the difference in R2* was not significant between the scanners (P<.0001 and P=.505, respectively) in vivo.

Conclusion

Both methods, M-HIC and R2*, are reliable iron concentration indicators with linear dependence on iron concentration in vivo and in vitro. The R2* method was found to be comparable among different scanners. Transferability testing is needed for the use of the methods at various scanners.     

Hankel and Toeplitz Transforms on H 1: Continuity, Compactness and Fredholm Properties

We revisit the boundedness of Hankel and Toeplitz operators acting on the Hardy space H ¹ and give a new proof of the old result stating that the Hankel operator H _a is bounded if and only if a has bounded logarithmic mean oscillation. We also establish a sufficient and necessary condition for H _a to be compact on H ¹. The Fredholm properties of Toeplitz operators on H ¹ are studied for symbols in a Banach algebra similar to C + H ^∞ under mild additional conditions caused by the differences in the boundedness of Toeplitz operators acting on H ¹ and H ². The first author was partially supported by the European Commission IHP Network “Harmonic Analysis and Related Problems” (Contract Number: HPRN-CT-2001-00273-HARP) and by the Greek Research Program “Pythagoras 2” (75% European funds and 25 National funds). The second author was fully supported by the European Commission IHP Network “Harmonic Analysis and Related Problems” (Contract Number: HPRN-CT-2001-00273-HARP) while he visited the first author at the University of Crete and later by the Academy of Finland Project 207048.     

On generalized Toeplitz and little Hankel operators on Bergman spaces

We find a concrete integral formula for the class of generalized Toeplitz operators \(T_a\) in Bergman spaces \(A^p\), \(1<p<\infty \), studied in an earlier work by the authors. The result is extended to little Hankel operators. We give an example of an \(L^2\)-symbol a such that \(T_{|a|} \) fails to be bounded in \(A^2\), although \(T_a : A^2 \rightarrow A^2\) is seen to be bounded by using the generalized definition. We also confirm that the generalized definition coincides with the classical one whenever the latter makes sense.     

Pendulum in a Fermi liquid

The Fermi-liquid theory formulated by Landau is a basic paradigm of the behavior of an interacting many-body system. We present a new application of this theory to calculate the "Landau force" on a macroscopic object. We show that immersing a pendulum in a Fermi liquid can increase its oscillation frequency, and evidence of this has been observed in mixtures of (3)He and (4)He.     

Properties of the 13/2+ isomeric decay in201Hg

The isomeric decay of theT _1/2=94 us isomeric state in²⁰¹Hg was studied in beam via the reaction¹⁹⁸Pt(α, n). Gamma-ray and conversion-electron spectra were recorded. From the conversion coefficients, the multipolarities of the two depopulating transitions were determined to beM 2 + 10%E 3 andE 2, respectively. These assignments give the depopulating transitions to be 13/2⁺ → 9/2^? and 9/2^? → 5/2^?, and these thus substantiate the previous suggestion that the isomeric state hasJ ^π=13/2⁺. For the 13/2⁺ → 9/2^? M 2 transition a detailed study ofE 3 andM 4 admixed amplitudes was done. The microscopic properties of the 13/2⁺ and 9/2^? states are discussed, and a comparison to the corresponding ones in^199,203,205Hg is made.     

Comparison of calculated DFT/B3LYP and experimental C and O NMR chemical shifts, ab initio HF/6-31G* optimised structures, and single crystal X-ray structures of some substituted methyl 5β-cholan-24-oates

Single crystal X-ray structures (monoclinic space group P2₁) for methyl 3-oxo-5β-cholan-24-oate and methyl 3,12-dioxo-5β-cholan-24-oate have been solved and compared with HF/6-31G* optimised structures. In the crystalline packings the side chains are connected with weak OC(sp³)HO-type of interactions between C25–H and C24–O–C25 and the keto ends with weak C(sp³)HO=C-type of interactions between C4–H and O=C3. The orientations of the side chains, which steric configurations are of great importance to the biological activity of the molecules, are compared with the experimental structure of methyl 3-hydroxy-5β-cholan-24-oate. Probable reasons for the observed differences are discussed. In addition, ¹³C and ¹⁷O NMR chemical shifts of methyl 3-oxo-5β-cholan-24-oate and methyl 3,12-dioxo-5β-cholan-24-oate as well as the epimeric methyl 3-hydroxy-5β-cholan-24-oate and methyl 3β-hydroxy-5β-cholan-24-oate have been calculated (DFT/B3LYP/6-311G*) and compared with the experimental values by linear regression analyses. In general, the correspondence between the theoretical and experimental parameters is good or excellent.