In Silico Analysis of the Ga3+/Fe3+ Competition for Binding the Iron-Scavenging Siderophores of P. aeruginosa-Implementation of Three Gallium-Based Complexes in the "Trojan Horse" Antibacterial Strategy.

The emergence of multidrug-resistant (MDR) microorganisms combined with the ever-draining antibiotic pipeline poses a disturbing and immensely growing public health challenge that requires a multidisciplinary approach and the application of novel therapies aimed at unconventional targets and/or applying innovative drug formulations. Hence, bacterial iron acquisition systems and bacterial Fe2+/3+-containing enzymes have been identified as a plausible target of great potential. The intriguing "Trojan horse" approach deprives microorganisms from the essential iron. Recently, gallium's potential in medicine as an iron mimicry species has attracted vast attention. Different Ga3+ formulations exhibit diverse effects upon entering the cell and thus supposedly have multiple targets. The aim of the current study is to specifically distinguish characteristics of great significance in regard to the initial gallium-based complex, allowing the alien cation to effectively compete with the native ferric ion for binding the siderophores pyochelin and pyoverdine secreted by the bacterium P. aeruginosa. Therefore, three gallium-based formulations were taken into consideration: the first-generation gallium nitrate, Ga(NO3)3, metabolized to Ga3+-hydrated forms, the second-generation gallium maltolate (tris(3-hydroxy-2-methyl-4-pyronato)gallium), and the experimentally proven Ga carrier in the bloodstream-the protein transferrin. We employed a reliable in silico approach based on DFT computations in order to understand the underlying biochemical processes that govern the Ga3+/Fe3+ rivalry for binding the two bacterial siderophores.

N-Methyl- and N-Phenylpiperazine Functionalized Styryl Dyes Inside Cucurbiturils: Theoretical Assessment of the Factors Governing the Host-Guest Recognition.

The family of cucurbiturils (CBs), the unique pumpkin-shaped macrocycles, has received great attention over the past four decades owing to their remarkable recognition properties. They have found diverse applications including biosensing and drug delivery technologies. The cucurbituril complexation of guest molecules can modulate their pKas, improve their solubility in aqueous solution, and reduce the adverse effects of the drugs, as well as enhance the stability and/or enable targeted delivery of the drug molecule. Employing twelve cationic styryl dyes with N-methyl- and N-phenylpiperazine functionality as probes, we attempted to understand the factors that govern the host-guest complexation of such molecules within CB[7] and CB[8] host systems. Various key factors determining the process were recognized, such as the pH and dielectric constant of the medium, the cavity size of the host, the chemical characteristics of the substituents in the guest entity, and the presence/absence of metal cations. The presented results add to our understanding (at the molecular level) of the mechanism of encapsulation of styryl dyes by cucurbiturils, thus shedding new light on various aspects of the intriguing complexation chemistry and the underlying recognition processes.

Theoretical Assessment of the Ligand/Metal/Quadruplex Recognition in the Non-Canonical Nucleic Acids Structures.

Quadruplexes (GQs), peculiar DNA/RNA motifs concentrated in specific genomic regions, play a vital role in biological processes including telomere stability and, hence, represent promising targets for anticancer therapy. GQs are formed by folding guanine-rich sequences into square planar G-tetrads which stack onto one another. Metal cations, most often potassium, further stabilize the architecture by coordinating the lone electron pairs of the O atoms. The presence of additional nucleic acid bases, however, has been recently observed experimentally and contributes substantially to the structural heterogeneity of quadruplexes. Therefore, it is of paramount significance to understand the factors governing the underlying complex processes in these structures. The current study employs DFT calculations to model the interactions between metal cations (K+, Na+, Sr2+) and diverse tetrads composed of a guanine layer in combination with a guanine (G)-, adenine (A)-, cytosine (C)-, thymine (T)-, or uracil (U)-based tetrad layer. Moreover, the addition of 4-(3,4-dihydroisoquinolin-2-yl)-2-(quinolin-2-yl)quinazoline to the modeled quadruplexes as a possible mechanism of its well-exerted antitumor effect is assessed. The calculations imply that the metal cation competition and ligand complexation are influenced by the balance between electronic and implicit/explicit solvation effects, the composition of the tetrad layers, as well as by the solvent exposure to the surrounding environment expressed in terms of different dielectric constant values. The provided results significantly enhance our understanding of quadruplex diversity, ligand recognition, and the underlying mechanisms of stabilization at an atomic level.

Cu+/Ag+ Competition in Type I Copper Proteins (T1Cu).

Due to the similarity in the basic coordination behavior of their mono-charged cations, silver biochemistry is known to be linked to that of copper in biological systems. Still, Cu+/2+ is an essential micronutrient in many organisms, while no known biological process requires silver. In human cells, copper regulation and trafficking is strictly controlled by complex systems including many cytosolic copper chaperones, whereas some bacteria exploit the so-called "blue copper" proteins. Therefore, evaluating the controlling factors of the competition between these two metal cations is of enormous interest. By employing the tools of computational chemistry, we aim to delineate the extent to which Ag+ might be able to compete with the endogenous copper in its Type I (T1Cu) proteins, and where and if, alternatively, it is handled uniquely. The effect of the surrounding media (dielectric constant) and the type, number, and composition of amino acid residues are taken into account when modelling the reactions in the present study. The obtained results clearly indicate the susceptibility of the T1Cu proteins to a silver attack due to the favorable composition and geometry of the metal-binding centers, along with the similarity between the Ag+/Cu+-containing structures. Furthermore, by exploring intriguing questions of both metals' coordination chemistry, an important background for understanding the metabolism and biotransformation of silver in organisms is provided.