Energetic and Geometric Characteristics of Substituents, Part 3: The Case of NO2 and NH2 Groups in Their Mono-Substituted Derivatives of Six-Membered Heterocycles

Substituted heterocyclic arenes play important roles in biochemistry, catalysis, and in the design of functional materials. Exemplary six-membered heteroaromatic molecules, that differ from benzene by inclusion of one heteroatom, are pyridine, phosphorine, arsabenzene, and borabenzene. This theoretical study concerns the influence of the heteroatom present in these molecules on the properties of substituents of two types: electron-donating (ED) NH2 group and electron-accepting (EA) NO2 group, attached at the 2-, 3-, or 4-position. The effect is evaluated by the energy of interaction (Erel) between the substituent and the substituted system and electronic properties of the substituents described by the charge of the substituent active region (cSAR) index. In addition, several geometric descriptors of the substituent and heteroaromatic ring, as well as changes in the aromaticity, are considered. The latter are assessed using the Electron Density of Delocalized Bonds (EDDBs) property of delocalized π electrons. The obtained results show that the electronegativity (EN) of the heteroatom has a profound effect on the EA/ED properties of the substituents. This effect is also reflected in the geometry of studied molecules. The Erel parameter indicates that the relative stability of the molecules is highly related to the electronic interactions between the substituent and the heteroarene. This especially applies to the enhancement or weakening of π-resonance due to the EN of the heteroatom. Additionally, in the 2-heteroarene derivatives, specific through-space ortho interactions contribute to the heteroatom effects.

Quantum-chemical investigation of interactions in supramolecular systems: cholesterol - bile acids - silica in aqueous solutions

Hypercholesterolemia significantly increases the risk of myocardial infarction associated with COVID-19. Along with pharmacological treatment, the possibility of the excretion of excess cholesterol from an organism by adsorption is also of great interest. The interaction of cholesterol with the surface of partially hydrophobized silica in aqueous solutions of bile acids was investigated by the PM7 method using the COSMO (COnductor-like Screening MOdel) solvation model. The distribution of electrostatic and hydrophobic potentials of molecules and complexes was calculated. The values of free Gibbs energy adsorption of bile acids on the surface of silica correlate with the distribution coefficients in the n-octanol-water system. The energy of interaction of cholesterol with bile acids affects its adsorption on silica. The stronger the bond of cholesterol with the molecules of bile acids, the less it is released from the primary micelles in solution and adsorbed on the surface.

Computational approach towards the design of artemisinin–thymoquinone hybrids against main protease of SARS-COV-2

Background The sanitary emergency installed in the world, generated by the pandemic of COVID-19, instigates the search for scientific strategies to mitigate the damage caused by the disease to different sectors of society. The disease caused by the coronavirus, SARS-CoV-2, reached 216 countries/territories, where about 199 million people were reported with the infection. Of these, more than 4 million died. In this sense, strategies involving the development of new antiviral molecules are extremely important. The main protease (Mpro) from SARS-CoV-2 is an important target, which has been widely studied for antiviral treatment. This work aims to perform a screening of pharmacodynamics and pharmacokinetics of synthetic hybrids from thymoquinone and artemisin (THY-ART) against COVID-19. Results Molecular docking studies indicated that hybrids of artemisinin and thymoquinone showed a relevant interaction with the active fraction of the enzyme Mpro, when compared to the reference drugs. Furthermore, hybrids show an improvement in the interaction of substances with the enzyme, mainly due to the higher frequency of interactions with the Thr199 residue. ADMET studies indicated that hybrids tend to permeate biological membranes, allowing good human intestinal absorption, with low partition to the central nervous system, potentiation for CYP-450 enzyme inhibitors, low risk of toxicity compared to commercially available drugs, considering mainly mutagenicity and cardiotoxicity, low capacity of hybrids to permeate the blood–brain barrier, high absorption and moderate permeability in Caco-2 cells. In addition, T1–T7 tend to have a better distribution of their available fractions to carry out diffusion and transport across cell membranes, as well as increase the energy of interaction with the SARS-CoV-2 target. Conclusions Hybrid products of artemisinin and thymoquinone have the potential to inhibit Mpro, with desirable pharmacokinetic and toxicity characteristics compared to commercially available drugs, being indicated for preclinical and subsequent clinical studies against SARS-CoV-2. Emphasizing the possibility of synergistic use with currently used drugs in order to increase half-life and generate a possible synergistic effect. This work represents an important step for the development of specific drugs against COVID-19.

FEATURES OF miRNA ASSOCIATIONS WITH mRNA OF MYOCARDIAL INFARCTION CANDIDATE GENES

Cardiovascular diseases, in particular myocardial infarction, are one of the most common causes of death in the world. To date, the risk assessment strategy infarction and post-infarction complications represent a significant problem sensitivity and predictive value of modern methods and markers, so the identification of new genetic markers is an actual problem. In this research, functionally significant candidate genes were studied, which are involved in the processes associated with the pathogenesis of myocardial infarction, in lipid metabolism, thrombus formation, endothelial dysfunction, and inflammatory reactions. However, in addition to genes, it has been determined that miRNA is also involved in the development of myocardial infarction by regulating the expression of target genes. This paper presents characteristics of miRNA interactions with mRNAs of candidate myocardial infarction genes. We have identified 34, 51 and 36 target genes that have miRNA binding sites in the 5'UTR, CDS, and 3'UTR regions, respectively. Based on the criteria chosen in our study, candidate genes were identified that have a free energy of interaction with miRNA equal to -120 kJ/mole and higher in the following associations: in 5’UTR - ID02142.3p-miR and ALDH2; ID00909.3p-miR and ALOX5; ID00216.3p-miR and CD40; ID01272.3p-miR and DDAH2; ID01774.5p-miR and IL6R; miR-6752-5p and KLF4; ID03332.3p-miR and LAMA3; ID02363.5p-miR and NOS3; ID02800.3p-miR and OPA1; ID01310.3p-miR and PDE4D; ID03397.3p-miR and PTGS2; ID01098.3p-miR and SERPINE1; ID01018.3p-miR and SGPP1; ID02430.3p-miR and SHH; ID01652.3p-miR and THBS1; ID01770.3p-miR and ZNF202; in CDS - ID00457.3p-miR and APOA1; ID00425.5p-miR and BTN2A1; ID01632.5p- miR and CCL5; ID02899.3p-miR and CDKN2B; miR-6894-5p and CYP1A2; ID01806.3p-miR and IL6R; ID01403.5p-miR and PLAUR; ID02950.3p-miR and SEMA3F; ID03332.3p-miR and SGPP1; ID02062.3p-miR and SIRT6; ID02050.3p-miR and TNF; ID01804.3p-miR and XBP1; ID00182.5p-miR and ZNF202; in 3’UTR - ID01293.5p-miR and SMTN; ID01882.5p-miR and TNNI3. The identified associations can be used as genetic markers in the diagnosis of myocardial infarction.

CHARACTERISTICS OF miRNA INTERACTION WITH mRNA OF ISCHEMIC HEART DISEASE CANDIDATE GENES

Ischemic heart disease (IHD) is the most serious cardiovascular disease and one of the leading causes of death worldwide. An important role in the pathophysiology of IHD play such processes as the processes of inflammation and immune response, metabolism of homocysteine and folate, development processes of endothelial dysfunction and oxidative stress and homeostasis system. Accordingly, the identified genes that are directly involved in these processes. In addition, miRNA (mRNA-inhibiting RNA) may affect the expression of these candidate genes. Using bioinformatics methods, the most efficient associations of miRNA and target genes were established. This research presents the characteristics of miRNA interactions with mRNA of candidate IHD genes. Candidate genes were identified that had a free energy of interaction with miRNA equal to -120 kJ / mole and higher in the following interactions: in 5’UTR - ALDH2 and ID02142.3p-miR; CELSR2 and ID00457.3p-miR; DDAH2 and ID01272.3p-miR; DNMT1 and ID02052.5p-miR; DOCK7 and ID00061.3p-miR; EGFR and ID02457.3p-miR; FOLH1 and ID01428.3p-miR; IL6R and miR-6089; NOS3 and ID02363.5p-miR; NPC1 and ID00551.3p-miR; PPP1R17 and ID01693.5p-miR; PRKCH and ID00520.5p-miR; SERPINE1 and ID01098.3p-miR; in CDS - ABCG8 and ID03064.3p-miR; ADORA2A and ID02697.3p-miR; APOA1 and ID00457.3p-miR; CDKN2B and ID02899.3p-miR; IL6R and ID01806.3p-miR; TIMP2 and ID00098.5p-miR; TNF and ID02050.3p-miR; TRIB1 and ID03208.5p-miR; VWF and ID01238.5p-miR. Associations were also revealed in the 3'UTR region with an interaction free energy of -115 kJ/mole and higher: AGTR2 and ID01213.5p-miR; APLNR and ID00616.5p-miR; CXCL12 and ID00483.3p-miR; FADS2 and miR-1224-3p; FCGR2A and miR-1273g-3p; GCKR and ID02928.3p-miR; IL6R and ID00913.5p-miR; KCNJ11 and ID03288.5p-miR; PPP1R3B and ID00913.5p-miR; TFPI and miR-1273g-3p; TIMP2 and ID01941.5p-miR. The results obtained could be used as molecular genetic markers of IHD for the diagnosis of this disease.

Developing a heap leaching technology for floating gold ores

The features of the technology of heap leaching with floating gold are disclosed. It was found that significant technological losses of gold in the processes of enrichment of gold-bearing ores, as a rule, are associated with its natural fine mineralization or technogenic transformation to such a state. It has been shown that flat gold flakes (even with a gold grain size of more than 1 mm) are quite well retained on the surface of technological solutions, i.e., have a certain buoyancy. The wettability of gold particles is explained by the manifestation of the surface tension forces of aqueous solutions, the mechanisms of which are determined by the van der Waals interaction. In addition, the wettability of gold grains is affected by their electric charge, which, accumulating on a convex surface, creates a negative charge that prevents the formation of a double electric field around the gold particle, which is an additional reason for the non-wettability of gold. The mechanism of the formation of gold films, which are formed at a high value of surface tension, with the formation of floating "islands" covered with a hydrophilic shell, is explained. It was revealed that the energy of interaction of a gold nanoparticle with water can serve as a quantitative indicator of the buoyancy of gold grains and "islands" of nanogold, at a value of which of 0.05427 eV, clearly pronounced hydrophilic properties appear. The theoretical substantiation of the buoyancy of gold grains and "islands" of nanogold is the van der Waals interaction. On this basis, heap leaching technology was developed, with the targeted deposition of floating gold in the most suitable places. As a result of a decrease in the surface tension of leaching solutions, nanogold loses their initial buoyancy and sink from them to the bottom, where they will be subjected to the processes of their disembarkation (collection and extraction).

Hydrogen isotope separation through bi-layer membranes

The quantum sieving mechanism through the bilayer membranes calculated on hydrogen isotopes is described. The technology for determining the potential energy of interaction of a monoatomic membrane is presented. The permeability of membranes obtained via the matrix method of solving the differential Schrödinger equation. It consists of using the linking technology at the boundaries of the calculated interval. The permeability of a bilayer graphidine membrane for hydrogen isotopes H2, D2, T2, HD is considered. The resonant regimes of the components passage are found and the conditions favorable for the separation of individual components from the mixture are determined. As a result, it has been shown that composite membranes are an effective way for isotope separation in the gas state at cryogenic temperatures.

THEORETICAL ELEMENTS OF ENERGY MODULAR LAYOUT OF AUTOMOBILE SYSTEM

The article presents a physical and mathematical model of the energy-modular configuration of a vehicle. A technique for modeling the motion of an automobile system with main connections based on the Lagrange equations is considered. This approach allows us to represent the model of the automotive system as a combination of two platforms, force factors and mechanical links, ensures their combination in one workflow. An equation has been drawn up and calculations have been carried out to change the kinetic energy for various modes of motion of the automobile system. The aim of the study is to improve the technology of moving the automotive system using a combination of two mobile platforms. The scientific and practical significance of the work lies in the fact that for the first time a technology has been proposed in which the energy of interaction of two platforms is used to move the automobile system. The research methodology was to establish a mathematical relationship between the generalized force and the dynamics of platform interaction, which is responsible for the movement of the automotive system. The result is the developed geometry of the interaction between platforms in the damping cycle of the interacting platforms. The value of the study, the results of the work carried out make it possible to contribute to the automotive industry. A model is proposed to reduce the energy to create vehicle motion.