Biomeditsinskaia Khimiia[JOURNAL]
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200 papers
Interaction of kidney proteins of normal and hypertensive rats with fragments of renalase peptide RP220.
Buneeva OA, Fedchenko VI, Kaloshina SA … +3 more , Zavyalova MG, Zgoda VG, Medvedev AE
Biomed Khim · 2025 Mar · PMID 40326017 · Publisher ↗
Renalase (RNLS) is a protein involved in the regulation of blood pressure; it has various functions inside and outside cells. The twenty-membered peptide RP220, corresponding to the amino acid sequence of human RNLS 220-...
Renalase (RNLS) is a protein involved in the regulation of blood pressure; it has various functions inside and outside cells. The twenty-membered peptide RP220, corresponding to the amino acid sequence of human RNLS 220-239, reproduces a number of effects of extracellular RNLS and can bind to many intracellular proteins in the kidney. The RP220 sequence contains several cleavage sites for extracellular proteases, which could potentially produce RP224-232 and RP233-239 peptides. The aim of this work was to perform proteomic profiling of kidney tissue from normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) derived from WKY, using potential proteolytic fragments (RP224-232 and RP233-239) of the RP220 peptide as affinity ligands, and to compare these proteomic profiles with the profiles obtained using the parent RP220 peptide. The obtained results indicate that the relative content of proteins bound to the RNLS peptides in SHR, compared to that in WKY rats, changes most significantly in the case of the RP224-232 peptide. Almost all of these proteins, with a few exceptions, are associated with cardiovascular pathology, many with hypertension. The results of our work indicate that proteolytic processing of RP220 does not lead to the inactivation of this peptide, but to a change in its ligand/regulatory properties, as well as the repertoire of potential protein partners and, consequently, protein-protein interactions that may have possible pharmacological application.
The study of the azithromycin effect on gene expression of the toll-like receptor system in the brain nucleus accumbens of rats during ethanol withdrawal and search for possible molecular targets by an in silico method.
Airapetov MI, Eresko SO, Shchukina AA … +5 more , Matveev NM, Andreev MA, Bychkov ER, Lebedev AA, Shabanov PD
Biomed Khim · 2025 Mar · PMID 40326016 · Publisher ↗
The brain's nucleus accumbens (NAc) is a key link in the internal reinforcement system, which mediates manifestations of various components of addiction, including ethanol. The neuroinflammatory theory of alcoholism deve...
The brain's nucleus accumbens (NAc) is a key link in the internal reinforcement system, which mediates manifestations of various components of addiction, including ethanol. The neuroinflammatory theory of alcoholism development suggests that changes in the molecular mechanisms of the innate immune system may be involved in the development of this pathology. The aim of our study was to investigate the effect of azithromycin (AZM) on expression of toll-like receptor system genes in the NAc during experimental alcoholization of rats. The objectives of the study also included an in silico search for possible molecular targets for AZM that could be associated with the toll-like receptor system. AZM corrected the changes observed in the expression of toll-like receptor system genes under conditions of alcohol withdrawal after long-term ethanol exposure in the NAc of the brain. The in silico analysis revealed the most probable proteins which could be involved in the interaction with AZM. Based on results of these predictions a number of assumptions about possible ways of implementing the observed pharmacological effect of AZM in the experiment have been made.
Slow-binding inhibitors of enzymes: kinetic characteristics and pharmacological interest.
Shaihutdinova ZM, Pashirova TN, Masson P
Biomed Khim · 2025 Mar · PMID 40326015 · Publisher ↗
Currently, the search for new slow-binding inhibitors of enzymes (SBI) and their identification primary in vitro studies still attracts much attention in the context of their potential role as putative pharmacological ag...
Currently, the search for new slow-binding inhibitors of enzymes (SBI) and their identification primary in vitro studies still attracts much attention in the context of their potential role as putative pharmacological agents for the treatment of various diseases. In contrast to their classical reversible analogues, SBI exhibit a slow enzyme binding kinetics, where the equilibrium steady-state is reached not in microseconds, but after longer time intervals. Such compounds could be promising drugs, because regardless of their pharmacokinetics in the bloodstream, they have such advantages as high affinity for the target enzyme, long residence time on the target, and therefore, prolonged action. These pharmacological properties ensure optimized dosage of drugs required to achieve high activity with less side effects. In this review we have considered mechanisms of SBI interaction with enzyme targets, the principles of their recognition at the level of in vitro studies and analysis of binding and kinetic parameters.
The study of biodegradation of galanin and its N-terminal fragments in a model system in vitro.
Avdeev DV, Selyutina OY, Sidorova MV … +1 more , Pisarenko OI
Biomed Khim · 2025 Feb · PMID 40045726 · Publisher ↗
Exogenous N-terminal fragments of galanin, which are agonists of the GalR2 receptor, have therapeutic potential in experimental cardiac pathology. This implies the need to study their proteolytic stability in biological...
Exogenous N-terminal fragments of galanin, which are agonists of the GalR2 receptor, have therapeutic potential in experimental cardiac pathology. This implies the need to study their proteolytic stability in biological environments. The aim of this work was to evaluate the proteolytic degradation of galanin G1 (GWTLNSAGYLLGPHAIDNHRSFSDKHGLT-NH2), its natural and modified fragments G2 and G3 (WTLNSAGYLLGPHA-OH and WTLNSAGYLLGPβAH-OH, respectively) in human plasma. The peptides were obtained by solid-phase synthesis using the Fmoc methodology, purified by HPLC; their structure was confirmed by MALDI-TOF mass spectrometry and 1H-NMR spectroscopy. The kinetics of galanins G1-G3 degradation in blood plasma was studied by 1H-NMR spectroscopy based on changes in the intensity of Trp2 signals at 310 K. The results indicate a higher proteolytic stability of the G3 peptide compared to the natural G2 fragment and full-length galanin G1. They indicate the potential of using modified peptide agonists of GalR2 receptors to protect vital organs in pathophysiological conditions.
Interaction of rat kidney proteins with the renalase peptide RP220 and its potential proteolytic fragment RP224-232: a comparative proteomic analysis.
Buneeva OA, Fedchenko VI, Gnedenko OV … +6 more , Kaloshina SA, Medvedeva MV, Zavyalova MG, Ivanov AS, Zgoda VG, Medvedev AE
Biomed Khim · 2025 Feb · PMID 40045725 · Publisher ↗
Renalase (RNLS) is a protein playing different roles inside and outside cells. A 20-mer synthetic peptide corresponding to the human RNLS amino acid sequence 220-239 (RP220) exhibits a number of pharmacologically attract...
Renalase (RNLS) is a protein playing different roles inside and outside cells. A 20-mer synthetic peptide corresponding to the human RNLS amino acid sequence 220-239 (RP220) exhibits a number of pharmacologically attractive activities in vitro and in vivo and can bind to many renal intracellular proteins. The RP220 sequence contains several cleavage sites for extracellular and circulating proteases. Here, we investigated the interaction of model proteins with the renalase peptide RP220 and a synthetic peptide corresponding to the amino acid sequence of RNLS 224-232, named RP224-232. We also performed affinity-based proteomic profiling of normotensive rat kidney samples with these peptides as affinity ligands. The obtained results indicate that both peptides exhibit almost the same affinity for model proteins (pyruvate kinase and lactate dehydrogenase), and the kidney proteomic profiles differ slightly. At the same time, the relative content of a number of kidney proteins bound to the RP224-232 peptide was even higher than in the case of using RP220. This suggests that proteolytic processing of RP220 does not inactivate this peptide; moreover, it could contribute to the formation of shorter peptides with additional pharmacological activities.
The SPR analysis of the interaction of inactivated poliovirus vaccine attenuated strains with antibodies.
Gnedenko OV, Ivin YY, Piniaeva AN … +8 more , Zyrina AN, Levin IV, Borisenko NS, Zhdanov DD, Ivanov AS, Lisitsa AV, Ishmukhametov AA, Archakov AI
Biomed Khim · 2025 Feb · PMID 40045724 · Publisher ↗
The interaction of inactivated poliovirus vaccine strains with oriented antibodies immobilized to protein A via Fc fragments has been investigated. Using an SPR biosensor, the kinetic and equilibrium parameters of the in...
The interaction of inactivated poliovirus vaccine strains with oriented antibodies immobilized to protein A via Fc fragments has been investigated. Using an SPR biosensor, the kinetic and equilibrium parameters of the interaction of vaccine attenuated polioviruses of the Sabin strains type 1 and type 2, inactivated by various methods were determined. The strongest interaction was observed between polyclonal antibodies to Sabin strain type 2 poliovirus and Sabin strain type 2 poliovirus inactivated with β-propiolactone, KD = 1.04⋅10-11 M, as well as the interaction of monoclonal antibodies to Sabin strain type 1 poliovirus and Sabin strain type 1 poliovirus inactivated with formaldehyde, KD = 1.39⋅10-11 M. The high-affinity interaction of inactivated vaccine polioviruses of the Sabin strains type 1 and type 2 with immobilized antibodies indicates that the D-antigen retained its structure after virus inactivation with β-propiolactone or formaldehyde.
The role of probiotics in the regulation of expression of genes supporting antioxidant status and functionality of mouse testes in LPS-induced inflammatory processes.
Babenkova PI, Chirkin EA, Syromyatnikov MY … +4 more , Zvereva OV, Tolkacheva AA, Korneeva OS, Gureev AP
Biomed Khim · 2025 Feb · PMID 40045723 · Publisher ↗
Systemic lipopolysaccharide (LPS)-induced inflammation has a significant impact on various organs, including the male reproductive system. In this study, we have demonstrated that LPS-induced inflammation causes oxidativ...
Systemic lipopolysaccharide (LPS)-induced inflammation has a significant impact on various organs, including the male reproductive system. In this study, we have demonstrated that LPS-induced inflammation causes oxidative stress in mouse testes, reduces expression of genes encoding the catalytic subunit of glutamate-cysteine ligase (Gclc) and superoxide dismutase 2 (Sod2). Inflammation suppressed transcription of genes involved in differentiation and metabolic regulation of testicular cells and sperm maturation: in the LPS group, the expression of the Amh, Lepr, Eif2b4 genes was approximately 3 times lower compared to the control group. The intake of probiotic microorganisms caused a decrease in the intensity of lipid peroxidation, which was manifested in a decrease in the level of conjugated dienes (CD) compared to the LPS group, contributed to maintaining the level of expression of genes supporting the antioxidant status, as well as genes supporting the functionality of the mouse testes. The data obtained suggest that probiotics may be considered as potential tools for maintaining male reproductive function under conditions of inflammatory processes.
The effect of addition of two targeted vectors, cRGD peptide and folic acid, with the same linker length on the properties of the doxorubicin phospholipid composition: a study of properties in vitro.
Kostryukova LV, Tereshkina YA, Bedretdinov FN … +1 more , Gisina AM
Biomed Khim · 2025 Feb · PMID 40045722 · Publisher ↗
Serious side effects of the chemotherapeutic drug doxorubicin prompt researchers to develop systems for its targeted delivery to cells. In this work, we continued the study on the effect of using two vectors in a phospho...
Serious side effects of the chemotherapeutic drug doxorubicin prompt researchers to develop systems for its targeted delivery to cells. In this work, we continued the study on the effect of using two vectors in a phospholipid delivery system of doxorubicin (Dox) for targeted therapy of breast cancer. We have obtained a composition NPh-Dox-cRGD-Fol(2.0) with the same linker length for both targeting ligands, cRGD and folic acid (PEG 2000). The resulting composition NPh-Dox-cRGD-Fol(2.0) with a particle size less than 50 nm and with 99% Dox incorporated into nanoparticles in an experiment on drug release at different pH values (5.0 and 7.4) showed a faster release and a high level of Dox compared to the phospholipid nanoform and a composition containing only the cRGD peptide. In vitro experiments on MDA-MB-231 breast cancer cells expressing the folate receptor and integrin αvβ3 demonstrated an increase in the total accumulation and internalization of Dox upon incubation with the dual-vector composition compared to the control samples. On the MCF-7 breast cancer cell line (expressing only the folate receptor), a similar effect was observed upon incubation with the single-vector composition containing folic acid (NPh-Dox-Fol(2.0)). In experiments with normal Wi-38 cell line, the internalization and total accumulation of the drug were comparable for both the free substance and the vector compositions. After 24 h-incubation of MDA-MB-231 cells with Dox-containing (10 μg/ml DOX) samples, the lowest percentage of living cells was observed for the studied dual-vector composition NPh-Dox-cRGD-Fol(2.0). On MCF-7 cells, the cytotoxic effect was manifested equally for the studied samples. The study of the cell death pathway on MDA-MB-231 cells showed the predominance of the apoptotic pathway (late apoptosis), while in the case of MCF-7 the necrosis pathway predominated. The cell cycle study performed using MDA-MB-231 cells (folate receptor (+) and integrin αvβ3 (+)) revealed an increase in the percentage of cells in the G0/G1 phase was noted thus indicating apoptotic cell death during incubation with NPh-Dox-cRGD-Fol(2.0). No differences were found between the samples in experiments performed on MCF-7 cells (folate receptor (+) and integrin αvβ3 (-)).
The inducing effect of S-nitrosoglutathione on the expression and activity of organic anion transporting polypeptide 1B1 (OATP1B1) in HepG2 cells.
Suchkova ON, Abalenikhina YV, Shchul'kin AV … +5 more , Myl'nikov PY, Gadzhiyeva FT, Kochanova PD, Uzbekov MG, Yakusheva EN
Biomed Khim · 2025 Feb · PMID 40045721 · Publisher ↗
The effect of the nitric oxide donor S-nitrosoglutathione on the level and activity of organic anion transporting polypeptide 1B1 (OATP1B1), as well as the expression of the SLCO1B1 gene encoding the transporter protein,...
The effect of the nitric oxide donor S-nitrosoglutathione on the level and activity of organic anion transporting polypeptide 1B1 (OATP1B1), as well as the expression of the SLCO1B1 gene encoding the transporter protein, was investigated in HepG2 cells. The study has shown that treatment of cells with S-nitrosoglutathione for 3 h did not influence the content and activity of OATP1B1. Incubation with S-nitrosoglutathione (10-500 μM) for 24 h increased SLCO1B1 expression, the content of OATP1B1, and activity of the transporter protein. Induction of the OATP1B1 protein by the NO donor was suppressed by the soluble guanylate cyclase (sGC) inhibitor, 10 μM ODQ (1H-[1,2,4]oxadiazolo-[4,3-a]quinoxaline-1-OH). Thus, the study has shown that S-nitrosoglutathione, acting through the NO-sGC-cGMP signaling pathway, increased SLCO1B1 gene expression, accompanied by the increase in the transporter protein content and its activity in cells.
The role of the PPM1D gene in tumor pathogenesis.
Kucheryavenko AS, Muzyko EA, Perfilova VN … +2 more , Kaplanov KD, Frolov MY
Biomed Khim · 2025 Feb · PMID 40045720 · Publisher ↗
The PPM1D gene and its protein product (serine-threonine protein phosphatase, PPM1D or Wip1) are involved in regulation of cell's DNA damage response, cell cycle control, and repair. Amplification, overexpression, or mut...
The PPM1D gene and its protein product (serine-threonine protein phosphatase, PPM1D or Wip1) are involved in regulation of cell's DNA damage response, cell cycle control, and repair. Amplification, overexpression, or mutations of the PPM1D gene have a significant impact on cell responses to stress factors and genetic instability as well as impairments of processes of double-strand break repair, nucleotide excision repair, base excision repair, cell cycle, and apoptosis. PPM1D dephosphorylates and thus inactivates p53, proteins that respond to DNA strand integrity damage, cell cycle checkpoint proteins, and apoptotic proteins. This contributes to tumor development, growth, and maintenance of the tumor phenotype. In this review we consider data on the role of the PPM1D gene in the formation and maintenance of various oncological processes, including tumors of the mammary glands, ovaries, prostate gland, esophagus, stomach, intestines, liver and pancreas, hemoblastoses, and others.
Biomarkers of hepatocellular carcinoma: status and prospects.
Zorina ES, Naryzhny SN
Biomed Khim · 2025 Feb · PMID 40045719 · Publisher ↗
Hepatocellular carcinoma (HCC) also known as hepatocellular cancer is one of the most common and aggressive types of primary malignant liver neoplasms. This type of cancer accounts for up to 90% of all primary liver tumo...
Hepatocellular carcinoma (HCC) also known as hepatocellular cancer is one of the most common and aggressive types of primary malignant liver neoplasms. This type of cancer accounts for up to 90% of all primary liver tumors and is the third leading cause of cancer death worldwide. Despite the advances in modern medicine, diagnostics and treatment of HCC remain challenging, especially in the later stages, when the patient's prognosis significantly worsens and treatment options are very limited. More than half a century has passed since Yu.S. Tatarinov discovered embryo-specific α-globulin in the blood of people with primary liver cancer in 1963, which was later called alpha-fetoprotein (AFP), but unfortunately, the number of specific and sensitive biomarkers for HCC remains very limited. In this regard, many scientific papers are devoted to the search and study of potential HCC biomarkers, which are essential for early diagnostics, prognosis, and development of new therapeutic strategies. Proteomic studies represent one of the promising approaches to investigate both molecular mechanisms of HCC occurrence and HCC biomarkers. Identification of specific protein profiles characteristic of tumor cells can contribute to the identification of new biomarkers that can be used not only for early detection of the disease, but also for monitoring its progression, assessing the response to therapy and predicting the clinical outcome. This review discusses current achievements in the search for potential biomarkers of HCC, as well as the prospects for their clinical use.
Identification of mouse brain proteoforms: comparison of 2D-electrophoresis data and independent experiment with mass spectrometric identification.
Rybina AV
Biomed Khim · 2024 Dec · PMID 39718111 · Publisher ↗
A previously developed algorithm for the preliminary identification of protein proteoforms associated with post-translational modifications (PTMs) based on 2D electrophoresis data (DOI: 10.18097/BMCRM00191) has been used...
A previously developed algorithm for the preliminary identification of protein proteoforms associated with post-translational modifications (PTMs) based on 2D electrophoresis data (DOI: 10.18097/BMCRM00191) has been used in this study for analysis of experimental data obtained using mice and reported in two papers by different authors. The authors of the first paper identified 8 groups of spots on 2D electrophoretic maps corresponding to 8 proteins with at least two unconcretised proteoforms. The authors of the second paper analyzed brain samples by means of the LC-MS/MS. In this study identification of peptides with PTMs was repeated using the raw data from the second paper. Among the 8 target proteins, 7 were identified in most of the biological samples. For 4 of them, 17 possible peptides with modifications were found. The 5 proteoform variants with identified PTMs matched the spots on the 2D electrophoresis maps. Thus, the prediction of pI values for proteins with hypothetical PTMs allows to form a set of hypotheses about the presence of particular proteoforms on the 2D electrophoretic maps.
Extracting information on virus-human interactions and on antiviral compounds based on automated analysis of large text collections.
Tarasova OA, Biziukova NY, Stolbova EA … +11 more , Stolbov LA, Taktashov RR, Karasev DA, Ionov NS, Ivanov SM, Dmitriev AV, Rudik AV, Druzhilovskiy DS, Sobolev BN, Filimonov DA, Poroikov VV
Biomed Khim · 2024 Dec · PMID 39718110 · Publisher ↗
The development of effective antivirals is of great importance due to the threat associated with the rapid spread of viral infections. The accumulation of data in scientific publications and in databases of biologically...
The development of effective antivirals is of great importance due to the threat associated with the rapid spread of viral infections. The accumulation of data in scientific publications and in databases of biologically active compounds provides an opportunity to extract specific information about interactions between chemicals and their viral and host targets. This information can be used for elucidation of knowledge about potential antiviral activity of chemical compounds, their side effects and toxicities. Our study aims to extract knowledge about virus-host interactions and potential antiviral agents based on the mining of massive amounts of scientific publications. With a set of previously developed algorithms, we have extracted comprehensive information on virus-host interactions and chemical compounds that interact with both viral and host targets. We collected data on the interactions of several viruses, including hepatitis B and C viruses, SARS-CoV-2, influenza A and B, and herpes simplex viruses, with (1) the host (human body), (2) potential antiviral agents, and, also extracted information on the interactions between potential antiviral agents and host proteins. Based on the data analysis performed, we created a freely available knowledge base on the interaction of chemical compounds with viral proteins and their host targets, allowing the exploration of both well-studied and recently discovered novel virus-host-chemical-compound interactions.
Homology modeling of the orthoflavivirus NS1 protein for virtual screening of potential ligands.
Fomina AD, Palyulin VA, Osolodkin DI
Biomed Khim · 2024 Dec · PMID 39718109 · Publisher ↗
The orthoflavivirus NS1 protein is a relatively understudied target for the design of broad-spectrum anti-orthoflaviviral drugs. Currently, the NS1 protein structures of tick-borne orthoflaviviruses have not been publish...
The orthoflavivirus NS1 protein is a relatively understudied target for the design of broad-spectrum anti-orthoflaviviral drugs. Currently, the NS1 protein structures of tick-borne orthoflaviviruses have not been published yet, but these structures can be modelled by homology, thus generating a large amount of structural data. We performed homology modelling of the NS1 protein structures of epidemiologically significant orthoflaviviruses and analysed the possibility of using these models in ensemble docking-based virtual screening. The limitations of the method and the importance of separating the models based on the vector organism when selecting an ensemble have been demonstrated.
The effect of bitter honey against cerebral malaria-induced inflammasome cell death: network pharmacology-based in silico evaluation.
Daniyan MO, Adeoye OB, Osirim E … +1 more , Asiyanbola ID
Biomed Khim · 2024 Dec · PMID 39718108 · Publisher ↗
Cerebral malaria (CM) is a fatal complication of Plasmodium falciparum infection. The biological and physiological links between CM, inflammation, and inflammasome, point to the complexity of its pathology. Resistance to...
Cerebral malaria (CM) is a fatal complication of Plasmodium falciparum infection. The biological and physiological links between CM, inflammation, and inflammasome, point to the complexity of its pathology. Resistance to available and affordable drugs, worsening economic crisis, and urgent need for integration of orthodox with traditional/alternative medicine, actualized the search for sustainable pharmacotherapy. Previous works from our team on the medicinal properties of bitter honey have established botanical and bioactive markers, inhibitory effects on pancreatic alpha-amylase activity, and anti-dyslipidemia, cardio-protective, and ameliorative effects on hepatorenal damage in streptozotocin-induced diabetic rats. In this study, we have identified bitter honey (BH) derived phytochemicals using gas chromatography coupled with mass spectrometry (GC-MS), and 9 targets from genes associated with CM, inflammation, inflammasome, and BH phytochemicals. Network analysis revealed significant functional and physical interactions among these targets and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3). Molecular docking of bitter honey-derived phytochemicals against these targets identified 3 most promising phytochemical candidates for further experimental validation. Based on these results, we predict that bitter honey may aid in the suppression of CM-mediated inflammasome cell death via its interactions with these targets.
Large-scale prediction of biological activities with Active-IT system.
Almeida VL, Dos Santos ODH, Lopes JCD
Biomed Khim · 2024 Dec · PMID 39718107 · Publisher ↗
Traditional testing methods in pharmaceutical development can be time-consuming and costly, but in silico evaluation tools can offer a solution. Our in-house Active-IT system, a Ligand-Based Virtual Screening (LBVS) tool...
Traditional testing methods in pharmaceutical development can be time-consuming and costly, but in silico evaluation tools can offer a solution. Our in-house Active-IT system, a Ligand-Based Virtual Screening (LBVS) tool, was developed to predict the biological and pharmacological activities of small organic molecules. It includes four independent modules for generating molecular descriptors (3D-Pharma), machine learning modeling (ExCVBA), a database of bioactivity models, and a prediction module. Activity data collected from the PubChem BioAssay database was used for modelling SVM and Naïve Bayes machine learning methods. Models have been constructed using a recursive stratified partition method and validated through an activity randomization (Y-random) process. Over 3500 bioassays were modeled, each comprising 30 SVM and 30 Naïve Bayes models and 60 randomized models. Bioassays with low performance or discrimination between regular and randomized were discarded. Using the Active-IT system we have evaluated three bioactive compounds of Ayahuasca tea. The predictions were thoroughly validated using known targets described in several public databases. The external validation results are noteworthy, with 16 of 33 (48.5% with p-value.
Multi-target neural network model of anxiolytic activity of chemical compounds using correlation convolution of multiple docking energy spectra.
Vassiliev PM, Perfilev MA, Golubeva AV … +2 more , Kochetkov AN, Maltsev DV
Biomed Khim · 2024 Dec · PMID 39718106 · Publisher ↗
Anxiety disorders are one of the most common mental health pathologies in the world. They require searc h and development of novel effective pharmacologically active substances. Thus, the development of new approaches to...
Anxiety disorders are one of the most common mental health pathologies in the world. They require searc h and development of novel effective pharmacologically active substances. Thus, the development of new approaches to the search for anxiolytic substances by artificial intelligence methods is an important area of modern bioinformatics and pharmacology. In this work, a multi-target model of the dependence of the anxiolytic activity of chemical compounds on their integral affinity to relevant target proteins based on the correlation convolution of multiple docking energy spectra has been constructed using the method of artificial neural networks. The training set of the structure and activity of 537 known anxiolytic substances was formed on the basis of the previously created database, and optimized 3D models of these compounds were built. 22 biotargets presumably relevant to anxiolytic activity were identified and their valid 3D models were found. For each biotarget, 27 multiple docking spaces have been formed throughout its entire volume. Multiple ensemble molecular docking of 537 known anxiolytic compounds into all spaces of relevant target proteins has been performed. The correlation convolution of the calculated energy spectra of multiple docking was carried out. Using seven training options based on artificial multilayer perceptron neural networks, the multi-target model of depending anxiolytic activity chemical compounds on 22 parameters of the correlation convolution of the multiple docking spectra energy was constructed. The predictive ability of the created model was characterized Acc = 91.2% and AUCROC = 94.4%, with statistical significance of p < 1×10⁻¹⁵. The found model is currently used in the search for new substances with high anxiolytic activity.
Conformational dynamics of the enzyme-substrate complex of protein kinase A with pseudosubstrate SP20 and adenosine triphosphate.
Mulashkina TI, Leonova MS, Khrenova MG
Biomed Khim · 2024 Dec · PMID 39718105 · Publisher ↗
The phosphorylation reaction, catalyzed by the enzyme protein kinase A (PKA), plays one of the key roles in the work of the glutamatergic system, primarily involved in memory functioning. The analysis of the dynamic beha...
The phosphorylation reaction, catalyzed by the enzyme protein kinase A (PKA), plays one of the key roles in the work of the glutamatergic system, primarily involved in memory functioning. The analysis of the dynamic behavior of the enzyme-substrate complex allows one to learn the mechanism of the enzymatic reaction. According to the results of classical molecular dynamics calculations followed by hierarchical clustering, the most preferred proton acceptor during the phosphorylation reaction catalyzed by PKA is the carboxyl group of the amino acid residue Asp166; however, the γ-phosphate group of ATP can also act as an acceptor.
Modeling, synthesis and in vitro testing of peptides based on unusual amino acids as potential antibacterial agents.
Sargsyan AS, Karapetyan LT, Mkhitaryan AV … +6 more , Stepanyan LA, Sargsyan TH, Danghyan YM, Sargsyan AV, Oganezova GG, Hovhannisyan NA
Biomed Khim · 2024 Dec · PMID 39718104 · Publisher ↗
Currently non-protein amino acids and synthetic peptides are widely used as blocks in drug design. Many proteases are of great interest for pharmacology due to their key role in various pathologies. Bacterial collagenase...
Currently non-protein amino acids and synthetic peptides are widely used as blocks in drug design. Many proteases are of great interest for pharmacology due to their key role in various pathologies. Bacterial collagenase (EC 3.4.24.3) is quite an attractive target for drug development as the inhibitors of bacterial collagenolytic protease may stop propagation of diseases caused by infections. The interaction of peptides containing unusual amino acids with Clostridium histolyticum collagenase has been evaluated by molecular docking followed by the measurement of enzyme inhibition by selected compounds. According to the docking analysis, 4 compounds were selected and synthesized for further research. Measurement of enzyme activity revealed that all tested compounds inhibited collagenase activity with IC50 values ranging within 1.45-2.08 μM. The antibacterial activity of synthesized compounds against some resistant strains was characterized by MICs values ranging within 4.6-9.2 μg/ml.
Repositioning of drugs for the treatment of major depressive disorder based on prediction of drug-induced gene expression changes.
Ivanov SM, Lagunin AA, Poroikov VV
Biomed Khim · 2024 Dec · PMID 39718103 · Publisher ↗
Major depressive disorder (MDD) is one of the most common diseases affecting millions of people worldwide. The use of existing antidepressants in many cases does not allow achieving stable remission, probably due to insu...
Major depressive disorder (MDD) is one of the most common diseases affecting millions of people worldwide. The use of existing antidepressants in many cases does not allow achieving stable remission, probably due to insufficient understanding of pathological mechanisms. This indicates the need for the development of more effective drugs based on in-depth understanding of MDD's pathophysiology. Since the high costs and long duration of the development of new drugs, the drug repositions may be the promising alternative. In this study we have applied the recently developed DIGEP-Pred approach to identify drugs that induce changes in expression of genes associated with the etiopathogenesis of MDD, followed by identification of their potential MDD-related targets and molecular mechanisms of the antidepressive effects. The applied approach included the following steps. First, using structure-activity relationships (SARs) we predicted drug-induced gene expression changes for 3690 worldwide approved drugs. Disease enrichment analysis applied to the predicted genes allowed to identify drugs that significantly altered expression of known MDD-related genes. Second, potential drug targets, which are probable master regulators responsible for drug-induced gene expression changes, have been identified through the SAR-based prediction and network analysis. Only those drugs whose potential targets were clearly associated with MDD according to the published data, were selected for further analysis. Third, since potential new antidepressants must distribute into brain tissues, drugs with an oral route of administration were selected and their blood-brain barrier permeability was estimated using available experimental data and in silico predictions. As a result, we identified 19 drugs, which can be potentially repurposed for the MDD treatment. These drugs belong to various therapeutic categories, including adrenergic/dopaminergic agents, antiemetics, antihistamines, antitussives, and muscle relaxants. Many of these drugs have experimentally confirmed or predicted interactions with well-known MDD-related protein targets such as monoamine (serotonin, adrenaline, dopamine) and acetylcholine receptors and transporters as well as with less trivial targets including galanin receptor type 3 (GALR3), G-protein coupled estrogen receptor 1 (GPER1), tyrosine-protein kinase JAK3, serine/threonine-protein kinase ULK1. Importantly, that the most of 19 drugs act on two or more MDD-related targets, which may produce the stronger action on gene expression changes and achieve a potent therapeutic effect. Thus, the revealed 19 drugs may represent the promising candidates for the treatment of MDD.
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