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A significant part of modern research is devoted to synthesis and study of the structure of compounds of rare earth elements with bioligands – these are those ligands that participate in biochemical processes. Compounds of rare earth elements with amino acids are of particular interest to study, since they are the most important bioligands, natural nanoscale molecules. In the course of the work, compounds of lanthanum (III) and cerium (III) with aspartic acid were synthesized. White crystalline precipitates were obtained for the «La-Asp» (1:2) and «Ce-Asp» (1:3) systems. With the help of optical microscopy, the fundamental difference between the crystals of synthesized compounds (in shape and size) from the crystals of the starting substances used for synthesis is proved. The results of IR-Fourier spectroscopy showed that metal ions interact with the carboxyl group of aspartic acid. The results obtained during the spectrophotometric analysis of the filler fluid for the «La-Asp» system (1:2) made it possible to simulate the spatial structure of this compound taking into account the amount of aspartic acid bound to lanthanum (III) ions. The synthesized compounds are promising for their further use in medicine.

Ion channels ensure the functioning of the nervous system because they are involved in the depolarization of neurons, axonal conduction and the release of neurotransmitters. They are located in the membranes of all excitable tissues and are involved in the mechanisms of nociception. Modulation of ion channel signaling by small molecules can be effective in inhibiting the course of pain syndromes of various etiologies. A small number of ion channels are currently identified as potential targets for the development of antinociceptive drugs, as evidenced by medicinal chemistry data and various biophysical and pharmacological studies. This review provides examples of selective cation channel modulators as novel therapeutic agents for analgesia and prospects for the creation of innovative channel-targeted analgesic drugs. [ABSTRACT FROM AUTHOR]

Introduction. Pathogens keep evolving and develop resistance to antimicrobial drugs. As a result, science is constantly searching for new antimicrobial agents. Their complex forms based on organic and inorganic ligands exhibit a stronger synergistic antimicrobial effect, if compared to free ligands. The Scopus database contains 73 thousand scientific articles about antimicrobial activity descriptors published during the last five years. This selection includes ten thousand reviews and three thousand publications that feature the antimicrobial activity of platinum complexes. The research objective was to screen the antimicrobial properties of platinum nitrite complexes. The present paper highlights some of the current domestic and foreign trends in this field of research: the biochemical synthesis of peptides as metabolites of bacteria; the development of anti-biofilm agents that act on the protective systems of pathogens; the creation of antimicrobial nanosystems; the synthesis of antimicrobial surfactants; the synthesis and study of the antimicrobial activity of platinum complexes, etc. The authors also give a brief description of the mechanisms of antibacterial action. Study objects and methods. Five previously synthesized complexes of platinum (II) and platinum (IV), both mononuclear and bionuclear, were tested for antimicrobial activity. The platinum complexes contained terminal and bridged nitrite ligands. The test cultures included Bacillus subtilis and Aspergillus niger. The experiment involved the disk-diffusion method and the macro method of serial dilutions. Results and discussion. All the complexes inhibited the metabolic growth of microorganisms to various degrees. The results depended on the composition and structure of the complex, the number and charge of the coordination centers, the degree of platinum oxidation, and the thermodynamic stability and lability of ligand bonds with the complexing agent. The response to Aspergillus niger proved more pronounced. The Pt+2 nonelectrolyte complex containing both terminal and bridged nitrite ligands was less active than the Pt+2 cationic complex, which contained only bridged NO2– ligands. The highest antibacterial activity belonged to the bionuclear complex of PtIV-PtII [(NH3)2(NO2)2PtIV(µ-NO2)2PtII(NH3)2](NO3)2 in relation to Bacillus subtilis B4647 and Aspergillus niger. The minimum inhibitory concentration (MIC) was > 125 μmol. Conclusion. The complexing resulted in a synergistic effect between the ligand and the complexing substance. The poly-core complexes contain two or more linked platinum centers that can covalently bind to DNA. They form a completely different type of DNA adducts compared to mononuclear complexes, as well as cross-links between DNA chains with fixation on different parts. The octahedral platinum complexes are kinetic and thermodynamically inert. Unlike similar squamous complexes, they proved to be able to act as prodrugs, recovering inside or outside the bacterial cell. The antimicrobial activity of the mixed-valence PtIV-PtII bionuclear complex [(NH3)2 (NO2)2PtIV(µ-NO2)2PtII(NH3)2](NO3)2 produced inhibitory effect comparable to the existing antimicrobial drugs. A further research will focus on composite mixtures of platinum complexes with other existing antimicrobial agents, as well as on other bacterial strains.

Experimental data were summarized to assume that dinitrosyl iron complexes (DNICs) with thiol-containing ligands are an endogenous "working form" of the nitric oxide (NO) system in living organisms. DNICs can function as donors of both neutral NO molecules, which are responsible for positive regulatory effects of the NO system on various physiological and biochemical processes in humans and animals, and nitrosonium cations (NO^(+)), which are responsible mostly for negative cytotoxic activity of the system. Special attention is paid to the finding that DNICs, especially in combination with dithiocarbamate derivatives, suppress SARS-CoV-2 infection in Syrian hamsters.

In this work, we synthesized and characterized the properties of a series of new fluorescent DB3(n) narrow-groove ligands. DB3(n) compounds based on dimeric trisbenzimidazoles have the ability to bind to the AT regions of DNA. The synthesis of DB3(n), whose trisbenzimidazole fragments are linked by oligomethylene linkers of different lengths (n = 1, 5, 9), is based on the condensation of the MB3 monomeric trisbenzimidazole with α,ω-alkyldicarboxylic acids. DB3 (n) proved to be effective inhibitors of the catalytic activity of HIV-1 integrase at submicromolar concentrations (0.20-0.30 μM). DB3(n) was found to inhibit the catalytic activity of DNA topoisomerase I at low micromolar concentrations.

The problem of ligand binding to certain receptor proteins is of central importance in cellular signaling, but it is still unresolved at a molecular level. In order to enhance our understanding of the molecular mechanisms we used a biophysical approach to study a serotonin-gated ion channel. The molecular model of 5-HT3 receptor extracellular domain was created using computer-based homology modeling. The docking method was used for building complexes of the 5-HT3 receptor and ligands. Some different activities were investigated by the method of molecular dynamics.

Immunotherapy of malignant tumors is a rapidly developing area of oncology. PD-1 is a receptor expressed by activated T-lymphocytes. As a result of its interaction with the ligand (PD-L1 or PD-L2), the activity of T-lymphocytes is inhibited and their apoptosis occurs. Drugs that inhibit the interaction of PD-1 with ligands have an immunostimulatory effect and are effective in the treatment of many types of neoplasms: melanoma, lung cancer, bladder cancer, stomach cancer, various lymphomas, etc. However, response to this treatment is observed only in a narrow cohort of patients. To increase the effectiveness of immunotherapy, combined preparations and nanoparticles are being developed and created to enhance the effect of PD-L1 inhibitors, and containing hyaluronic acid as a ligand for the CD44 protein, which is expressed in many human tumors. However, the issue of co-expression of CD44 and PD-L1 remains poorly understood. This review is devoted to describing the features of co-expression and the mechanisms of interaction between CD44 and PD-L1. Promising directions for the development of new approaches to the immunotherapy of malignant tumors are presented.

The paper analyzes a set of equations that adequately predict the IC50 value for SARS-CoV-2 main protease inhibitors. The training set was obtained using filtering by criteria independent of prediction of target value. It included 76 compounds, and the test set included nine compounds. We used the values of energy contributions obtained in the calculation of the change of the free energy of complex by MMGBSA method and a number of characteristics of the physical and chemical properties of the inhibitors as independent variables. It is sufficient to use only seven independent variables without loss of prediction quality (Q² = 0.79; R²prediction = 0.89). The maximum error in this case does not exceed 0.92 lg(IC50) units with a full range of observed values from 1.26 to 4.95.

Among the repertoire of MarR family transcriptional regulators in Mycobacterium tuberculosis, gene rv3095 (mxyR) encodes Mycobacterial Xylan Regulator, MxyR. Gene mxyR is divergently oriented from a hydrolase (rv3094c), oxidoreductase (rv3093c) and an ABC transporter (rv3092c) and convergently oriented with xylanase (rv3096). Xylanase is commonly used by plant pathogenic microbes where they degrade xylan, the major component of hemicellulose. We have purified the transcriptional regulatory protein encoded by rv3095 and its molecular interactions were studied in detail using electrophoretic mobility shift assay. MxyR interacts with its upstream intergenic region mxyO with high specificity and at a dissociation constant of 5.01 ± 0.017 nM. Notably, this binding is attenuated by specific carbohydrate ligands such as xylan, L-Arabinose and D-Galactose with an IC50 values of 22.7 ± 1.02 ng/μL, 360.8 ± 24.25 ng/μL and 2320.0 ± 96.97 μg/μL, respectively. Consequently, it is evident that this association changes the conformation of the DNA binding helix α4 making the transcriptional regulator incompatible with binding to its cognate DNA, allowing xylanase and other genes to be transcribed. This study establishes the natural ligands of MxyR of M. tuberculosis providing insight on metabolic regulation of the carbohydrate, xylan.

G-quadruplexes (G4), non-canonical secondary DNA structures, are intensively investigated for a long time. In eukaryotic organisms they play an important role in the regulation of gene expression and DNA repair. G4 have also been found in the genomes of numerous bacteria and archaea, but their functional role has not yet been fully explored. Nevertheless, their participation in the formation of antigenic variability, pathogenicity, antibiotic resistance and survival in extreme conditions has been established. Currently, many tools have been developed to detect potential G4 sequences and confirm their formation ability. Since the controlled formation and resolution of the quadruplex are significant means for the regulation of genes critical for survival, a promising direction is the search for ligands - compounds that can have a stabilizing effect on the quadruplex structure and thereby alter gene expression. Currently, a number of ligands are already known, their use stops the growth of pathogenic microorganisms. G4 ligands are of interest as potential antibiotics, which are extremely relevant due to the wide spread of drug resistant pathogens.

Immune checkpoint inhibitors (ICIs), including cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed death protein 1 (PD-1) or its ligand (PD-L1), are a new generation of immuno-oncological drugs that to date have demonstrated efficacy in a number of malignancies. The mechanism of ICT inhibitors action consist in the potentiation of the immune response by eliminating the tumor cells inhibitory effect on the T-lymphocytes activation. However, excessive immune system activation can cause the development of a special class of immune-related adverse events (irAEs) involved a wide variety of organs and systems, including the kidneys. Despite the fact that immuno-mediated kidney injury caused by ICI therapy develops quite rarely, it can be serious and determine the patient's prognosis, which necessitates early diagnosis and timely start of treatment. In this regard, awareness of the manifestations of ICI-associated renal irAEs is particularly relevant not only for oncologists and for nephrologists, but for doctors of other specialties. In this review, we elucidated the main variants of immuno-mediated kidney injury caused by ICI therapy, discussed possible predictors and mechanisms of their development, and considers the general principles of diagnosis and management of patients according to the severity of irAEs.

Ionotropic glutamate receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype play a key role in synaptic plasticity representing one of the mechanisms for learning and memory formation. They can also serve as targets for the development of novel classes of pharmaceuticals for the treatment or substantive correction of many serious neurodegenerative and psychoneurological disorders. The search and studies of various types of AMPA receptor ligands attract considerable attention from academic organizations and pharmaceutical companies all over the world. This review mainly focuses on recent advances in this field. The architecture and operational mechanism of the receptor as well as its major binding sites and ligand types are considered. Special attention is paid to the studies of mechanisms of action and novel chemotypes of AMPA receptor agonists and competitive antagonists, positive and negative allosteric modulators, auxiliary protein-dependent allosteric modulators, and ion channel blockers.

Objective: To study the conjugate dynamics of vascular endothelial growth factor (VEGF) and the components of metal-ligand homeostasis in the development of ischemic stroke., Material and Methods: The main group included patients with ischemic stroke ( n =158). The comparison group consisted of healthy volunteers ( n =150). The concentration of VEGF (pg/ml) in the blood serum was determined by ELISA and concentrations of Mg, Cu, Mn, Se, Zn and Fe (mcg/ml) by inductively coupled argon plasma mass spectrometry. Data analysis was carried out using the Statistica 10 application software package and the optimal reliable partitioning (SDR) method, which is part of the Date mining group of data mining methods., Results: A significant increase in the concentrations of VEGF and trace elements Mg, Mn, Cu, Zn, and Se in the blood serum of patients with ischemic stroke was revealed. A significant relationship between the concentration of VEGF and the concentrations of Cu and Mn in the blood serum of patients with ischemic stroke was shown., Conclusion: The dynamics of VEGF and the concentrations of trace elements in the development of the ischemic process contribute to the solution of therapeutic and prognostic problems in clinical conditions.

It is important to understand the features of the interaction of drug components with body receptors and obtain data on its distribution in various administration routes in recommended doses in order for its usage in clinical practice to be safe and effective., Purpose: To investigate in vitro the interactions of a drug consisting of water-soluble polypeptide fractions produced on animal retina with a wide range of receptor targets, and to assess its biodistribution in the organs of laboratory animals., Material and Methods: The biodistribution of the radioactively marked drug in different organs and tissues of laboratory mice in various routes of administration was studied at the National Research Centre «Kurchatov Institute». Evaluation of the ligand-receptor interaction of the drug was carried out in the laboratory at Eurofins Pharma Discovery Services by the method of competitive radioligand binding., Results: A significant effect of the interaction of the polypeptide drug was revealed with different subtypes of glutamate receptors: AMPA, NMDA, and mGluR1. As a result of an in vivo test, we have obtained biodistribution data of the drug for intravenous, intramuscular and parabulbar administration, and the dynamics of drug accumulation in the tissues of the brain and eyes., Conclusion: According to the study results, the peptide drug binds to receptors associated with the loss of retinal ganglion cells. Interaction with these receptors potentially provides the test subject with neuroprotective effect. The content dynamics of the studied drug in the blood of animals depends on the route of administration and the amount of drug administered. At the time point of 0.5 hours for intravenous and intramuscular administration in the dose of 1.7 mg/kg, the studied drug has sufficiently high bioavailability in the tissues of the brain and eye. The data suggest that the main route of excretion of the studied drug is through kidneys.

Several variants of models for predicting the IC50 values of inhibitors of influenza virus neuraminidase are presented for both individual strains and for combinations of data for neuraminidases of several strains. They are based on the use of calculated energy contributions to the amount of change in the free energy of enzyme-inhibitor complexes. In contrast to previous works, aimed at the complex modeling, we added a procedure of comparison of the docking variants with one of the neuraminidase inhibitors, for which the structure of the complexes was determined experimentally. The choice of the comparison structure was made according to the similarity of structures evaluated using the Tanimoto metrics and the limit of the RMSD value for a similar part of the structure was no more than 2 Å. Using this limitation and filtering datasets for a particular strain by the Q2 value obtained in the leave-one-out control procedure it is possible to construct equations for predicting the IC50 value with a Q2 value close to the minimum confidence threshold (0.57 in this work). Taking into consideration that in this version of the prediction, a minimum set of energy contributions is used, which does not provide for expensive calculations of entropy contributions, the result obtained supports the correctness of using a generalized model based on the data on the position of known ligands to predict the inhibition of neuraminidase of the influenza virus of various strains.

The leukotriene B4 receptors BLT1 and BLT2 are promising targets for the treatment of allergic and inflammatory diseases. However, no working model of ligand binding to either of these receptors has been developed so far. Under the assumption that homologous receptors bind their ligands in a similar way, computational modeling of agonist binding to BLT1 and BLT2 was performed using fully flexible docking in Galaxy 7TM. For both receptors, the carboxyl group of the ligand forms a salt bridge with an arginine residue, while the tail hydroxyl groups form hydrogen bonds with three amino acid residues. The differential specificity of ligands to BLT1 and BLT2 is explained by the replacement of histidine with tyrosine. In BLT1, the histidine residue binds the 5-OH group of the ligand, while the tyrosine residue in BLT2 repels it. The presented models are in agreement with experimental data and may be useful for developing new BLT1- and BLT2-targeted drugs.

New drug discovery is based on the analysis of public information about the mechanisms of the disease, molecular targets, and ligands, which interaction with the target could lead to the normalization of the pathological process. The available data on diseases, drugs, pharmacological effects, molecular targets, and drug-like substances, taking into account the combinatorics of the associative relations between them, correspond to the Big Data. To analyze such data, the application of computer-aided drug design methods is necessary. An overview of the studies in this area performed by the Laboratory for Structure-Function Based Drug Design of IBMC is presented. We have developed the approaches to identifying promising pharmacological targets, predicting several thousand types of biological activity based on the structural formula of the compound, analyzing protein-ligand interactions based on assessing local similarity of amino acid sequences, identifying likely molecular mechanisms of side effects of drugs, calculating the integral toxicity of drugs taking into account their metabolism, have been developed in the human body, predicting sustainable and sensitive options strains and evaluating the effectiveness of combinations of antiretroviral drugs in patients, taking into account the molecular genetic characteristics of the clinical isolates of HIV-1. Our computer programs are implemented as the web-services freely available on the Internet, which are used by thousands of researchers from many countries of the world to select the most promising substances for the synthesis and determine the priority areas for experimental testing of their biological activity.

Traditionally, the thermodynamic values of affinity are considered as the main criterion for the development of new drugs. Usually, these values for drugs are measured in vitro at steady concentrations of the receptor and ligand, which are differed from in vivo environment. Recent studies have shown that the kinetics of the process of drug binding to its receptor make significant contribution in the drug effectiveness. This has increased attention in characterizing and predicting the rate constants of association and dissociation of the receptor ligand at the stage of preclinical studies of drug candidates. A drug with a long residence time can determine ligand-receptor selectivity (kinetic selectivity), maintain pharmacological activity of the drug at its low concentration in vivo. The paper discusses the theoretical basis of protein-ligand binding, molecular determinants that control the kinetics of the drug-receptor binding. Understanding the molecular features underlying the kinetics of receptor-ligand binding will contribute to the rational design of drugs with desired properties.

We present a novel computational ligand-based virtual screening approach with scaffold hopping capabilities for the identification of novel inhibitors of β-lactamases which confer bacterial resistance to β-lactam antibiotics. The structures of known β-lactamase inhibitors were used as query ligands, and a virtual in silico screening a database of 8 million drug-like compounds was performed in order to select the ligands with similar shape and charge distribution. A set of numerical descriptors was used such as chirality, eigen spectrum of matrices of interatomic distances and connectivity together with higher order moment invariants that showed their efficiency in the field of pattern recognition but have not yet been employed in drug discovery. The developed scaffold-hopping approach was applied for the discovery of analogues of four allosteric inhibitors of serine β-lactamases. After a virtual in silico screening, the effect of two selected ligands on the activity of TEM type β-lactamase was studied experimentally. New non-β-lactam inhibitors were found that showed more effective inhibition of β-lactamases compared to query ligands.

The paper presents the results concerning the application of docking programs FLM to combined use of the MMFF94 force field and the semiempirical quantum-chemical method PM7 in the docking procedure. At the first step of this procedure a fairly wide range of low-energy minima of the protein-ligand complex is found in the frame of the MMFF94 force field using the FLM program. The energies of all these minima are recalculated using the PM7 method and the COSMO solvent continuum model at the second step. On the basis of these calculations the deepest minimum of the protein-ligand energy, calculated by the PM7 method with COSMO solvent, is determined, which gives the position of the ligand closest to its position in the crystal of the protein-ligand complex. It is shown that the first step of the combined procedure is performed more quickly and more efficiently in vacuum, rather than with a solvent model.

The paper focuses on intermolecular interactions, particularly interactions between proteins and natural intermediates (small molecules). Molecules with a molecular weight of up to 1000 Da are free in cytoplasmic solution and form a pool of intermediates. Methods of computer modeling for prediction of protein-proteinaceous, protein-ligand, protein - a small molecule of interactions are presented. The program for modeling predicted biological activity in silico is Prediction of Activity Spectrum for Substances (PASS). In the Search Tool for Interacting Chemicals (STITCH) system, it is possible to identify potential protein interaction partners for small molecules. A review of the literature presents modern data on small molecules - metabolic switches, such as α-glycerophosphatedihydroxyacetone phosphate, pyruvate-lactate, oxaloacetate-malate. The molecules we study have different and multiple effects on metabolism and on intercellular interaction systems. Natural intermediates are at the intersection of metabolic pathways of metabolism of proteins, carbohydrates, lipids; they are signal molecules, participate in regulation of protein function, gene expression, enzyme activity. An increasing interest in deciphering protein-small molecule/metabolite interactions at the systemic level will lay a conceptual foundation that provides insight into complex epigenetic regulation under various environmental influences. A complete interplay, including a protein-small molecule interaction, will be crucial to eventually unraveling the complex relationships between the genotype and phenotype and to provide a deeper understanding of health and disease., Competing Interests: The authors declare no conflict of interest.

Aryl-hydrocarbon receptor (Aryl Hydrocarbon Receptor, AHR) is a ligand-dependent transcription factor, whose functions are related to xenobiotic detoxification, response to inflammation, and maintenance of tissue homeostasis. Recent investigations suggest that AHR also plays an important role in the processes of carcinogenesis. Increased expression of AHR is observed in several types of tumors and tumor cell lines. In addition, it turned out that the composition of pharmaceutical drugs used in oncotherapy includes some ligands AHR. These facts allow us to consider an aryl-hydrocarbon receptor as a potential target for anticancer therapy, especially for the treatment of severe cancers whose treatment options are very limited or do not exist at all. In this review the examples of AHR ligands' effect on tumor cell cultures and on model mice lines with AHR-dependent response are discussed.

Composite sequence-specific ligands with DNA-damaging groups may dramatically increase the efficacy of radiotherapy. The most promising damage sensitizers are the atoms of heavy elements, in which electrons are emitted from upper orbitals and a multiply charged positive ion forms when an electron is kicked out from lower orbitals. The biophysical mechanisms of DNA damage produced by these sensitizers are far from fully understood. In this work, high-performance polyacrylamide gel electrophoresis (PAGE) in denaturing gel was used to investigate the nature of DNA cleavage on exposure to β radiation for complexes of heavy atom-containing ligands with DNA restriction fragments. It was demonstrated for the first time that DNA in complexes with Pt-bis-netropsin or mercury salts is cleaved in the vicinity of the heavy atom in the presence of radioactive isotopes emitting β particles of different energies. In the presence of 1 M glycerol, the cleavage of the DNA sugar-phosphate backbone was almost entirely due to a neutralization of the multiply charged Auger ion and was not associated with the Auger electron electron-beam radiolysis. Based on the observations, a relatively simple technique was proposed for precise localization of binding sites for various DNA ligands containing a heavy atom. Analysis of the end groups at the cleavage point and the nature of damage to the complementary DNA chain made it possible to speculate about the mechanisms of direct influence of irradiation on a heavy atom.

Isatin (indol-2,3-dione) is an endogenous indole found in the brain, peripheral tissues and biological body fluids of humans and animals. Its wide spectrum of biological activity is realized via interaction with numerous isatin-binding proteins; these include proteins playing an important role in the development of neurodegenerative pathology. In the context of the neuroprotective effect, the effect of isatin is comparable to the effects of deprenyl, a pharmacological agent used for treatment of Parkinson's disease. In this study, the effects of the course of deprenyl (1 mg/kg) and isatin (20 mg/kg) administration for 21 days on the profile of the isatin-binding proteins of the liver of mice have been investigated. Proteomic profiling of liver isatin-binding proteins of control mice by means of 5-aminocaproylisatin as an affinity ligand resulted in identification of 105 proteins. Treatment of animals with a low dose of isatin slightly decreased (up to 91), while injections of deprenyl slightly increased (up to 120) the total number of isatin-binding proteins. 75 proteins were common for all three groups; they represented from 62.5% (in deprenyl treated mice) and 71% (in control mice), to 82% (isatin treated mice) of the total number of identified liver isatin-binding proteins. Proteomic analysis of the isatin-binding proteins of mice treated with isatin (20 mg/kg) or deprenyl (1 mg/kg) for 21 days revealed a representative group of proteins (n=30) that were sensitive to the administration of these substances. Taking into account the previously obtained results, it is reasonable to suggest that the change in the profile of isatin-binding proteins may be attributed to accumulation of isatin and deprenyl in the liver and interaction with target proteins prevents their subsequent binding to the affinity sorbent. In this context, the identified isatin-binding liver proteins of control animals that do not bind to the affinity sorbent (immobilized isatin analogue) after treatment of animals with either deprenyl or isatin appear to be specific targets directly interacting with isatin in vivo.

Ligand binding influences the dynamics of the DNA helix in both the binding site and adjacent regions. This, in particular, is reflected in the changing pattern of cleavage of complexes under the action of ultrasound. The specificity of ultrasound-induced cleavage of the DNA sugar-phosphate backbone was studied in actinomycin D (AMD) complexes with double-stranded DNA restriction fragments. After antibiotic binding, the cleavage intensity of phosphodiester bonds between bases was shown to decrease at the chromophore intercalation site and to increase in adjacent positions. The character of cleavage depended on the sequences flanking the binding site and the presence of other AMD molecules bound in the close vicinity. A comparison of ultrasonic and DNase I cleavage patterns of AMD-DNA complexes provided more detail on the local conformation and dynamics of the DNA double helix in both binding site and adjacent regions. The results pave the way for developing a novel approach to studies of the nucleotide sequence dependence of DNA conformational dynamics and new techniques to identify functional genome regions.

Cytostatic colchicine is widely used in the treatment of Familial Mediterranean fever, but it has several side effects. For finding new, more effective drugs with higher affinity and diminishside effects we carried out virtual screening of potential inhibitors of the main target of colchicine, the polymerization of tubulin by evaluating affinity 25745 compounds, structurally related to the colchicine. We have identified 11 commercially available compounds with higher affinity to tubulin. Compounds with highest binding scores include trimethoxybenzene and its derivatives; these compounds bind to the same site in similar orientation. Information provided can form the basis for design of new cytostatics.

Aim: To study the influence of adenosine receptor ligands and hypoxic preconditioning on carbohydrate metabolism in global brain ischemia., Material and Methods: The study included 51 outbred white male mice weighing 20-25 g. An effect of adenosine receptor ligands and hypoxic preconditioning on brain tissue metabolism, heat exchange and longevity was explored., Results and Conclusion: Adenosine, an agonist of A1 adenosine receptors, and hypoxic preconditioning exert a neuroprotective effect on brain cells. The blocker of A1 adenosine receptors aggravates metabolic disturbances in the brain and removes the protective effect of cyclopenyladenosine and ischemic preconditioning.