Theoretical analysis of peptidyl alpha-ketoheterocyclic inhibitors of human neutrophil elastase: Insight into the mechanism of inhibition and the application of QM/MM calculations in structure-based drug design

It has been suggested from QSAR data (P. D. Edwards, D. J. Wolanin, D.A. Andisik and M. W. Davis, J. Med. Chem., 1995, 38, 76) that the inhibition of elastase by peptidyl alpha-ketoheterocyclic inhibitors can occur in two ways, the less potent inhibitors forming a non-bonded Michaelis complex and the more potent set a covalently bonded enzyme-substrate intermediate. We report QM/MM studies of both binding and reactivity that confirm these findings, showing that the activity of the least potent set of inhibitors correlates with the calculated binding energy, and that of the more potent set correlates with the stability of the intermediate. These calculations show that QM/MM methods can be successfully employed to understand complicated structure-activity relationships and might be employed in the design and assessment of new inhibitors.     

Physical properties of mixtures of low molar mass nematic liquid crystals with photochromic fulgide guest dyes

Abstract

This paper considers how a low concentration (> 2 per cent w/w) of a photochrome dissolved in a liquid crystal affects the physical properties of the host mesogen. A novel class of photochromes, the fulgide based dyes, have been used to give a new approach in this area of study. Unlike many other light active dyes, the fulgides exhibit only a relatively small shape change. Because of this, the influence of the changes in the physical properties of the guest (for example, the dipole moment) are readily studied. Both thiophene and furan fulgide doped liquid crystal systems were studied in the irradiated and non-irradiated states and as a function of concentration. The changes in phase transition temperature, refractive index and order parameter for these various states as compared to the pure host liquid crystal have been measured to investigate the way in which the dye alters the mesomorphic properties of the host, on a molecular level.     

The influence of pretransitional phenomena on blue phase range

Abstract

The particular phase in which a liquid crystal system will exist is that which has the lowest free energy at a certain temperature. The free energy may depend on variables such as temperature, pressure, chirality, etc. One way in which the stability of a particular thermodynamic phase, relative to its neighbours, would be manifest is in its temperature range. The effect of chirality, in particular, on the temperature range or stability of blue phases has been well-studied both experimentally and theoretically. To date these studies assume that chirality is the only parameter which will influence the existence of blue phases. However, blue phases with relatively low chirality and broad range, which should in principle only show very narrow blue phases, have been reported. This suggests that factors other than chirality are involved in blue phase stability. In this paper we investigate the phase stability of various blue phase mixtures containing equal amounts of a chiral dopant, via their blue phase temperature range. Correlation between blue phase stability and the elastic constants k ₂ and k ₂₂, molecular length of the nematic host, and the order parameter at the blue phase to cholesteric transition is discussed. We have confirmed that for our mixtures the total blue phase temperature range may be related equally to the elastic constant k ₂₂ and the chirality. We also present the first data displaying an odd-even effect in blue phases. Finally, we have found an apparent correlation between the stability of the blue phases and the magnitude of the orientational order parameter of the cholesteric phase at the cholesteric to blue phase transition.     

Laser-induced concentric colour domains in a cholesteric liquid crystal mixture containing a nematic azobenzene dopant

The isothermal formation of concentric colour domains has been observed in a cholesteric mixture doped with 10 wt % of a photochromic nematic material. The host cholesteric mixture included the Merck materials BL131a and BL130, while the photochromic dopant was a mixture of 4-n-butyl-4′-n-alkoxyazobenzenes (BAAB). The helical pitch of the host cholesteric mixture was increased, as expected, on addition of the photochromic nematic material prior to irradiation with the molecules in the purely trans-configuration. On irradiation with low power (0.6 mW) argon ion laser light, cis-isomers formed within the interaction region and concentric colour domains appeared. Selective reflection from the colour domains occurred in the 400–560 nm spectral range. The coloured domains persisted in the time period following irradiation and extended beyond the interaction region because of diffusion of the cis-isomers. Using the diffusion equation, an expression has been obtained for the average concentration of cis-isomers in each of the coloured domains and the dependence of the reflection wavelength upon the concentration of cis-isomers has been determined.     

Using the full Raman depolarisation in the determination of the order parameters in liquid crystal systems

The depolarisation ratio for the Raman-active phenyl stretching mode has been measured over the whole of the mesophase range, and the orientational order parameters deduced, in the uniaxial nematic liquid crystal octylcyanobiphenyl (8CB). Linearly polarised light was incident normally on a homogeneously aligned sample and a χ² minimisation routine performed on the 360^° depolarisation ratio profile. The order parameters 〈P ₂₀₀〉 and 〈P ₄₀₀〉 , together with the differential polarisability ratio, r , are used as fitting parameters and measured as a function of temperature. Interestingly, we show that the value for r , conventionally measured in the isotropic phase and assumed to remain constant, has a clear temperature dependence, ranging from -0.032±0.008 in the isotropic phase through to -0.245±0.015 at the nematic-to-smectic A phase transition. The measured order parameters 〈P ₂₀₀〉 and 〈P ₄₀₀〉 varied from 0.35- 0.55±0.02 and 0.180- 0.245±0.02 , respectively, across the 8 ^° C wide nematic phase range. The values of both 〈P ₂₀₀〉 and 〈P ₄₀₀〉 are in excellent agreement with theory, but it is noteworthy that 〈P ₄₀₀〉 shows a much better quantitative match than has been reported in previous work. Crucially the temperature dependence of r is shown to be a contributing factor in the low 〈P ₄₀₀〉 values that have been conventionally reported from Raman scattering measurements. The potential for fitting the entire angular depolarisation ratio distribution in liquid crystalline systems that are described by more order parameters, specifically biaxial materials, is discussed.     

Hydrogen interaction with EUVL-relevant optical materials

Mo/Si multilayer mirrors were exposed to deuterium ions with well-defined energies in order to gain insight into the effects of Extreme UV light driven plasma generation on reflective elements in commercial lithography equipment. Post-irradiation analysis by Rutherford Backscattering Spectrometry showed erosion of both Mo and Si layers for the highest energy 50 eV/D and exposure time 5.4 × 10⁴ s. Nuclear Reaction Analysis revealed detectable deuterium retention for energies ⩾25 eV/D. Surface analysis by X-ray Photoelectron Spectroscopy showed erosion of the first Si layer for energies ⩾5 eV/D. Inferences on the spatial distribution of trapped deuterium are made on the basis of available data regarding deuterium retention in the materials in question.     

Synthesis,cytotoxicity and antibacterial studies of symmetrically and non‐symmetrically benzyl‐ or p‐cyanobenzyl‐substituted N‐Heterocyclic carbene–silver complexes

From the reaction of 1H‐imidazole ( 1a ), 4,5‐dichloro‐1H‐imidazole ( 1b ) and 1H‐benzimidazole ( 1c ) with p‐cyanobenzyl bromide ( 2 ), symmetrically substituted N‐heterocyclic carbene (NHC) [( 3a–c )] precursors, 1‐methylimidazole ( 5a ), 4,5‐dichloro‐1‐methylimidazole ( 5b ) and 1‐methylbenzimidazole ( 5c ) with benzyl bromide ( 6 ), non‐symmetrically substituted N‐heterocyclic carbene (NHC) [( 7a–c )] precursors were synthesized. These NHC? precursors were then reacted with silver(I) acetate to yield the NHC‐silver complexes [1,3‐bis(4‐cyanobenzyl)imidazole‐2‐ylidene] silver(I) acetate ( 4a ), [4,5‐dichloro‐1,3‐bis(4‐cyanobenzyl)imidazole‐2‐ylidene] silver(I) acetate ( 4b ), [1,3‐bis(4‐cyanobenzyl)benzimidazole‐2‐ylidene] silver(I) acetate ( 4c ), (1‐methyl‐3‐benzylimidazole‐2‐ylidene) silver(I) acetate ( 8a ), (4,5‐dichloro‐1‐methyl‐3‐benzylimidazole‐2‐ylidene) silver(I) acetate ( 8b ) and (1‐methyl‐3‐benzylbenzimidazole‐2‐ylidene) silver(I) acetate ( 8c ) respectively. The four NHC‐precursors 3a–c, 7c and four NHC–silver complexes 4a–c and 8c were characterized by single crystal X‐ray diffraction. The preliminary antibacterial activity of all the compounds was studied against Gram‐negative bacteria Escherichia coli, and Gram‐positive bacteria Staphylococcus aureus using the qualitative Kirby‐Bauer disc‐diffusion method. All NHC–silver complexes exhibited medium to high antibacterial activity with areas of clearance ranging from 4 to 12 mm at the highest amount used, while the NHC‐precursors showed significantly lower activity. In addition, all NHC–silver complexes underwent preliminary cytotoxicity tests on the human renal‐cancer cell line Caki‐1 and showed medium to high cytotoxicity with IC₅₀ values ranging from 53 ( ± 8) to 3.2 ( ± 0.6) µM. Copyright © 2010 John Wiley & Sons, Ltd.     

Prediction of the potency of inhibitors of adenosine deaminase by QM/MM calculations

QM/MM calculations show that the potency of a range of inhibitors of adenosine deaminase correlates with the relative stability of the reaction intermediate at the active site, rather than with the inhibitor binding energy.