When biomolecules meet 2-hydrazinopyrazine: from theory through experiment to molecular levels using a wide spectrum of techniques.

The design of drug structures that are non-toxic, easily transported and permeable to cellular barriers is currently one of the most growing research trends. Indeed, the structural similarity of 2-hydrazinopyrazine (2HP) to pyrazinamide, which has been successfully used in anti-tuberculosis therapy, makes 2HP a promising research object. Thus, herein, a complete analysis of the structure of 2HP and its physicochemical and cytotoxic properties was performed. Calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) binding studies were conducted, which demonstrated the higher affinity of 2HP to BSA. Furthermore, cytotoxicity tests were performed, which proved that 2HP was non-toxic to human skin keratinocyte cells. Accordingly, 2HP was initially classified as a compound with potential application. Physicochemical investigations were performed using a wide range of experiments, which were supported by DFT calculations using the B3LYP functional and 6-311+G** basis set. The good correlation, high quality and correctness of the obtained parameters were proven although the data was obtained using independent techniques. Additionally, 42 tautomeric (prototrophic) forms of 2HP were found by searching the conformational hyperspace. The most energy stable 2HP conformer structure and the partial charge distribution were established. The preferred 2HP ionic forms preferred were presented, and models of the equilibrium occurring in aqueous solution were proposed. The hydrophilic character of 2HP was established based on the partition coefficient values determined by both experiment and theory. The PCM and SMD solvent models of water and n-octanol were used.

Calculations of pKa Values of Selected Pyridinium and Its N-Oxide Ions in Water and Acetonitrile.

Pyridine, its N-oxide, and their derivatives are exciting classes of organic bases. These compounds show widespread biological activity, and they are often used in synthesis. In this work results on theoretical calculations of acid dissociation constants as pKa of pyridine, its N-oxide, and their derivatives were done based on the thermodynamic cycle in water and acetonitrile. Additionally, gas-phase basicity (GB) and proton affinity (PA) values were computed for systems studied. All pKa values were obtained using B3LYP, M06-2X, and G4MP2 methods in the gas phase, which were combined with the PCM model calculations (at the Hartree-Fock method) and with the use of four different scale factors alpha. Theoretical GB, PA, and pKa values were then compared with the available experimental ones. Results obtained from B3LYP and M06-2X methods are quite similar and compatible with experimental ones in terms of quality with correlation coefficients values R2 higher than 0.9, whereas results received from G4MP2 deviate strongly. The calculated pKa values are highly sensitive to the scale factors alpha used in the computational procedure. Root-mean-square deviations (RMSD) between both theoretically and experimentally available pKa values of systems studied were also computed. The RMSD values are lower than 0.8 for the best results, suggesting that the theoretical model presented in this work is promising for applications for pKa calculations of different classes of compounds.

Introduction of Phosphorylated Residues into the UNRES Coarse-Grained Model: Toward Modeling of Signaling Processes.

Phosphorylated proteins take part in many signaling pathways and play a key role in homeostasis regulation. The all-atom force fields enable us to study the systems containing phosphorylated proteins, but they are limited to short time scales. In this paper, we report the extension of the physics-based coarse-grained UNRES force field to treat systems with phosphorylated amino-acid residues. To derive the respective potentials, appropriate physics-based analytical expressions were fitted to the potentials of mean force of systems modeling phosphorylated amino-acid residues computed in our previous work and implemented in UNRES. The extended UNRES performed well in ab initio simulations of two miniproteins containing phosphorylated residues, strongly suggesting that realistic large-scale simulations of processes involving phosphorylated proteins, especially signaling processes, are now possible.

Development and testing of a framework for analysing health literacy in public policy documents.

Health literacy is a driver of community empowerment and a key determinant of health and equity. The World Health Organisation has established a strong global mandate for addressing health literacy through public policy action, by positioning it as one of three key pillars for achieving sustainable development and health equity in the Shanghai Declaration on Health Promotion. Policy document analysis is a useful way of determining the strengths and limitations of past and current policies, as well as the likely success of their implementation and impact on health outcomes. In this study, we developed a framework for analysing policy documents to assess the extent to which they prioritise and operationalise an emergent public health issue, in this case health literacy. Specifically, the framework enables a systematic exploration of (i) the stated policy goals and strategic objectives; (ii) the stated policy actions; and (iii) whether there is an intention to resource and monitor the stated policy activities. We tested the utility of the framework by applying it to a set of public policies in the Australian context. The framework presented in this study may be a useful tool for systematically analysing policy documents to reveal their strengths and limitations, and the extent to which they prioritise and operationalise health literacy.