-Leucinyl benzenesulfonamides have been discovered as a novel class of potent inhibitors of leucyl-tRNA synthetase. The binding of inhibitors to the enzyme was measured by using isothermal titration calorimetry. This provided information on enthalpy and entropy contributions to binding, which, together with docking studies, were used for structure-activity relationship analysis. Enzymatic assays revealed that-leucinyl benzenesulfonamides display remarkable selectivity for leucyl-tRNA synthetase compared to and human orthologues. The simplest analogue of the series, -leucinyl benzenesulfonamide (R = H), showed the highest affinity against leucyl-tRNA synthetase and also exhibited antibacterial activity against Gram-negative pathogens (the best MIC = 8 μg/mL, ATCC 25922), which renders it as a promising template for antibacterial drug discovery.
Updated models of the Rat Cytochrome P450 2D enzymes are produced based on the recent x-ray structures of the Human P450 2D6 enzyme both with and without a ligand bound. The differences in species selectivity between the epimers quinine and quinidine are rationalised using these models and the results are discussed with regard to previous studies. A close approach to the heme is not observed in this study. The x-ray structure of the enzyme with a ligand bound is shown to be a better model for explaining the observed experimental binding of quinine and quinidine. Hence models with larger closed binding sites are recommended for comparative docking studies. This is consistent with molecular recognition in Cytochrome P450 enzymes being the result of a number of non-specific interactions in a large binding site.
The thermal decomposition of polyphenolic resins was studied by reactive molecular dynamics (RMD) simulation at elevated temperatures. Atomistic models of the polyphenolic resins to be used in the RMD were constructed using an automatic method which calls routines from the software package Materials Studio. In order to validate the models, simulated densities and heat capacities were compared with experimental values. The most suitable combination of force field and thermostat for this system was the Forcite force field with the Nosé-Hoover thermostat, which gave values of heat capacity closest to those of the experimental values. Simulated densities approached a final density of 1.05-1.08 g/cm 3 which compared favorably with the experimental values of 1.16-1.21 g/cm 3 for phenol-formaldehyde resins. The RMD calculations were run using LAMMPS software at temperatures of 1250 K and 3000 K using the ReaxFF force field and employing an in-house routine for removal of products of condensation. The species produced during RMD correlated with those found experimentally for polyphenolic systems and rearrangements to form cyclopropane moieties were observed. At the end of the RMD simulations a glassy carbon char resulted. mixtures were also investigated by van Duin [13]. A new force field was derived for Pt-O systems by Fantauzzi et al. [14], and an organic mechanistic study was carried out on polymerization by Schoenfelder [15]. Adaptive accelerated RMD on hydrogen was published by Goddard et al. [16], and an implementation of RMD on GPU's was developed by Kylasa et al. [17]. The second generation of RMD methods were reviewed by Farah et al. in 2012 [18], which used empirical reactive force fields to generate the new species. Recently, a transferable reactive force field was developed by Xiao, Shi, Hao, Liao, Zhang, and Chen for phosphorous and hydrogen which showed a distinct improvement in predicting the mechanical properties of pristine-and defect-laden black phosphorous [19]. In this study we concentrate on phenol-formaldehyde resins (PFRs), also known as phenolic resins, which are a subclass of synthetically derived thermosetting polymers obtained from a reaction of phenol with formaldehyde ( Figure 1).
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