Modern drug discovery primarily concentrates on identifying and understanding drug-target interactions. Traditional techniques, limited by factors like throughput, precision, and cost, struggle to efficiently identify these potential drug-target interactions. Hence, there's a pressing need for advanced computational methods to verify these drug-target relationships.

We constructed a deep learning model for drug-target interaction prediction. The features of target proteins were extracted and associated with drug molecular substructure fingerprints to form feature vectors of drug-target pairs. The features of compounds and target proteins were subsequently compressed into a unified vector space using sparse principal component analysis. Finally, we used a long short-term memory (LSTM) neural network to make predictions. Five-fold cross-validation was employed to evaluate the performance of our model.

Upon evaluation, our model showcased satisfactory performance in drug-target interaction prediction. Specifically, it achieved accuracies of 86.7%, 84.7%, and 73.4%. These scores were obtained from three different drug-target datasets, highlighting the model's robustness and generalizability. The slight variation in accuracy scores across datasets suggests that, while the model is highly effective, there might still be room for further optimization, particularly for datasets with unique characteristics. These findings indicate that the method is competitive with other contemporary drug-target prediction tools.

Proteins are an important part of blood plasma and perform various functions necessary for the proper functioning of the body. Both alpha-1 acid glycoprotein (AGP) and plasma albumin (HSA) are responsible for drug binding and transport.

Modern technologies combining knowledge from various fields are used in drug design. A popular method is QSAR, i.e. determining the relationship between the structure of a molecule and its activity. It uses statistical methods and extensive databases of chemical compounds.

In the present study, the binding of substances to plasma proteins was examined by HPLC. The results obtained during the study were subjected to statistical analysis. The influence of the nature of the substance on binding to proteins was demonstrated using ANOVA. The examination of the percentage of binding to plasma proteins (PB) for the log k retention value showed the greatest importance of HSA as the protein responsible for this pharmacokinetic phenomenon and the smaller contribution of AGP. However, in multiple regression models, the best results were obtained for basic drugs, indicating their high affinity for AGP.

The results of the conducted study provide a lot of valuable information regarding therapeutic substances. This confirms the theory that the HPLC method in combination with statistical analysis can be an important part of preclinical QSAR studies.

Autodisplay was used for the co-display of GluN1 and GluN2A ligand binding domains (LBDs) of the N‑methyl-D-aspartate (NMDA) receptor in E. coli. LBDs were confirmed to be located at the cell surface and form dimers, similar to local LBD heterodimers present in full-length NMDA receptors. Flow cytometry was used to evaluate binding of fluorescently labeled TCN‑201 derivatives to cells with co-displayed LBDs. TCN-201 is a negative allosteric modulator of GluN2A containing NMDA receptors that binds at the LBD heterodimer interface of GluN1 und GluN2A. Among three TCN-201 derivatives, compound 8 was identified as a novel ligand that bound to cells co-displaying both LBDs but not to cells displaying exclusively one type of LBDs. This was to indicate that compound 8 addressed the same binding site as TCN-201. An apparent dissociation constant of 6.8 ± 1.6 µM for compound 8 was determined. Two-electrode voltage-clamp experiments showed that compound 8 did not inhibit GluN1/GluN2A NMDA receptor-mediated currents. However, compound 8 abolished the current inhibition by TCN-201, indicating competitive binding to the same binding site. Subunit selectivity of compound 8 was evaluated by fluorescence staining of recombinant NMDA receptors in mouse L(tk-) cells. Here, selective staining of GluN2A in contrast to GluN2B containing NMDA receptors with compound 8 was confirmed. Additionally, staining was prevented by preincubation with TCN-201, once more reaffirming the competitive binding mode. This work describes the identification of compound 8 which appears to be the first fluorescent small molecule labeling compound that selectively addresses GluN2A containing NMDA receptors.

Development of an effective antiviral drug is typically followed by expansion of the successful strategy with numerous chemical variations of compounds providing improvements in parameters including affinity, solubility, lipophilicity, pharmacology, toxicity, drug resistance profiles etc. The aim of this study was to investigate the antiviral properties of newly synthesized fluorine-, chlorine-, and bromine-containing heterocyclic compounds against adeno-, herpes-, and influenza viruses. Cytotoxicity and antiviral efficacy of compounds was determined using a tetrazolium-based colorimetric and yield reduction assays, respectively. It should be noted that viability results were dependent on the type of used cells (CC₅₀ value of compounds was in range 167-2570 µg/mL). However, compound 3-(difluoromethyl)-2H-benzo[4,5]imidazole[1,2-b][1,2,6]thiadiazine-4-carbonitrile 1,1-dioxide (1792) was significantly toxic for cells of human laryngeal carcinoma which may indicate its antitumor properties. It was found that compound 5,7-dimethyl-4,7-dihydropyrazolo[4,3-e][1,2,4]thiadiazine1,1-dioxide with 3-(difluoromethyl), 3-(dichloromethyl) or 3-(trichloromethyl) substituents (1784, 1779 and 1781, respectively) inhibited HAdV-2 development of virus cytopathic effect on cells up to 49% and decreased infectious titer of virus obtained de novo by 1-5 log₁₀TCID₅₀/mL. Instead, significant antiinfluenza activity was observed for compound 1792, that decreased IAV reproduction up to 73%. Whereas for herpetic infection, antiviral effect of compounds was not detected, as the reduction of infectious titer did not exceed 0.6 log₁₀TCID₅₀/mL. Obtained data indicate that synthesized compounds may be promising antiviral agent. Furthermore, we showed that incorporation of the fluorine or chlorine atoms in molecule of compound significantly impact on its cytotoxicity and antiviral potency.

VCs show a wide range of pharmacological properties; the most important application in medicine is for the treatment of cancer and diabetes. The VCs therapeutic action may be associated with their binding to proteins. For this reason, the characterization of VCs/protein interactions is important. Among the most promising VCs, dioxidovanadium(V) complex with the aroylhydrazone furan-2-carboxylic acid 3-ethoxy-2-hydroxybenzylidene)hydrazide (GSW-4) deserves to be mentioned. GSW-4 is cytotoxic for several cancer cell lines, including HeLa. The interaction of GSW-4 with the model protein hen egg white lysozyme (HEWL) was studied by X-ray crystallography. X-ray diffraction data, collected under two different experimental conditions, reveal that GSW-4 and V-containing fragments derived from this molecule bind the protein through non-covalent interactions with the side chains of Arg5, Cys6, Glu7 and Lys33. On the protein surface, a GSW-4 molecule forms a supramolecular association with another GSW-4 unit through a Na⁺ ion. The supramolecular assembly is stabilized by stacking interactions. The reactivity of GSW-4 with HEWL could help in understanding of transport and mechanisms of action of this molecule, promoting the development of new compounds as therapeutic agents.

Prenatal hypoxia (PH) is a leading factor in the disorders of fetal CNS development and can lead to death or significant neuropsychiatric pathologies in children. Aim of ourstudy: to identify and evaluate the prognostic role of markers of neurodegeneration/neuroplasticity and indicators of endothelial dysfunction in the assessing the efficiency of therapy of PH damage consequences. In the experimental model of chronic nitrite-induced PH we studied the dynamics of markers of neurodegradation/neuroplasticity and indicators of endothelial dysfunction in offspring in the early postnatal period. The relationship between neurodegradation/neuroplasticity and endothelial dysfunction indicators and clinical characteristics of children with cerebral insufficiency after PH action was also investigated It was found that neurotrophic factors and heat shock proteins, as well as factors induced by hypoxia, are the key neuromolecules that have the ability to resist the mechanisms of neurodestruction. Dysfunction in the synthesis of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) may contribute to brain development with impaired neuroplasticity, leading to the formation of cerebral insufficiency in children after PH. Here we show the neuroprotective role of HSP70 and HIF-1a under conditions of PH. A direct correlation between HSP70 concentration, intensity of neurological disorders and the level of specific markers of neurodegeneration has been established. HSP70 modulators can be considered as promising neuroprotectors in the complex therapy of children after PH.

The ever-growing antibiotic resistance to currently prescribed antibiotics constitutes a main reason for investigating natural compounds for antibacterial action. Natural products can be used as leads for new synthetic antibacterial agents or as a source of novel bioactive compounds. Cinnamaldehyde and colupulone were selected as lead compounds for the purposes of this study. Cinnamaldehyde, a byproduct of the stem bark of Cinnamomum cassia, was isolated in 1834 by Jean-Baptiste Dumas, with uses ranging from the food and cosmetics to pharmaceutical industries. Colupulone, is a known hop b-acid found in Humulus lupulus, a plant also used in the pharmaceutical and food industry. Previous studies have shown that both compounds exhibit antibacterial properties. In order to investigate essential structures responsible for enhanced action, some functionalities on the selected parental compounds, cinnamaldehyde and colupulone, were preserved while others altered. Synthesis of these analogues was based on short synthetic routes, including efficient methods like Wittig reaction, Fries rearrangement and C-alkylation of phloroglucinol derivatives. Subsequent testing for their antibacterial action against gram-positive and gram-negative microorganisms Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa revealed important functionalities required for increased activities. The prospective development of a ligand-based pharmacophore was also investigated, by analyzing the structural-activity relationship of their bacterial growth inhibitory potencies. Enhance inhibitory action was observed for the para-methoxy analogue of trans-cinnamaldehyde against E.coli. In addition, all tested colupulone analogues exhibited enhanced activities for both E. coli and S.aureus. These results set the base for designing new compounds to better understand structure-activity relationship and improve activity.

Conversion of energy-storing white adipose tissue into energy-burning beige adipose tissue, called browning, has emerged as a promising approach in the field of metabolic research and obesity treatment. Adeno-associated viruses (AAV) are widely used as viral vectors for gene delivery in eucaryotic cells. This study focused on the efficacy of transduction of AAV 2/5, 2/6, 2/8 expressing GFP in 3T3-L1 murine preadipocyte cells by live imaging microscopy using IncuCyte S3. Three transduction modes were assessed: AAVs transduction in 3T3-L1 preadipocyte cells with or without further differentiation into mature adipocyte-like cells and injection of AAVs in differentiated adipocyte-like cells. The differentiation of 3T3-L1 was induced by adipogenic IBMX-DEX-INS cocktail. AAV2/6 demonstrated the highest transduction efficiency in 3T3-L1 preadipocytes, as it was 1.5–2-fold more effective than AAV2/5 and AAV2/8 in the range of viral concentration from 2×10⁴ to 8×10⁴ VG/cell. AAV2/5 and AAV2/8 showed the transduction efficiency similar to each other. The expression of GFP under CMV promoter remained stable up to 20 days. The induction of 3T3-L1 differentiation in three days after AAVs transduction didn’t alter the GFP expression level and AAV2/6 showed the highest transduction efficiency. AAV2/6 demonstrated ability to transduce mature adipocytes as well. Thus, AAV2/6 compared to AAV2/5 and AAV2/8 demonstrated the higher transduction efficacy in 3T3-L1 preadipocytes and mature adipocytes, which proved its usability along with AAV8 and AAV9 for gene delivery to adipocytes.

Sunlight exposure can cause skin damage, like sunburn, skin dryness, wrinkles hyperpigmentation and skin sensitivity reactions. The use of aftersun products is a strategy that minimizes the visible signs and symptoms of sun-damaged skin, once that photo-damaged skin is more susceptible to inflammaging and oxidative stress events, affecting the skin's repair mechanisms. Aiming to unveil the active ingredients able to counteract acute sun damage, this work focuses on the characterization of the aftersun products market. Aftersun formulations currently marketed in Portuguese pharmacies were analysed concerning the composition described on the product´s label. Natural-derived extracts and pure compounds, as well as synthetic compounds, with anti-photodamage activity were found. The majority of the aftersun formulations contained natural-derived ingredients (> 95%), from terrestrial (77%) and marine (4%) sources. An in-depth examination of these compounds is also disclosed, revealing the top of the most used natural and synthetic ingredients present in aftersun products, as well as their mechanism of action. A critical appraisal of the scientific data supporting their efficacy, together with some considerations concerning structure-activity relationship studies were carried out. The presence of terpenoid, guanidine, ester, amide, ureido moiety, carboxylic acid and alcohol functions were found in the cosmetic ingredients most used in aftersun products, allowing the correlation with their bioactivities. In summary, this work provides an overview of the use of actives in commercial aftersun products in order to better understand the benefits associated with their use in cosmetic formulations, concomitantly identifying opportunities for innovation.

Tyrosyl DNA phosphodiesterase 1 (Tdp1) is a promising target for the treatment of cancer, since it plays a key role in the removal of DNA damage generated by the action of topoisomerase 1 (Top1) poisons (irinotecan and topotecan) widely used in anticancer therapy. We have previously shown that the Tdp1 inhibitor, enamine derivative of usnic acid, the agent OL9-116, enhances the antitumor activity of topotecan and studied the pharmacokinetics of the agent. In the present study, we developed and validated an LC-MS/MS methods for the quantification of OL9-116 in mouse lungs, liver, kidneys, Lewis lung carcinoma tumor nodes and studied its distribution in organs of healthy and tumor mice. QuEChERS methodology was selected for sample preparation. Quantification of the compound was performed using SCIEX 6500 QTRAP mass spectrometer in MRM mode following chromatographic separation on a C8 reversed-phase column. Pharmacokinetics of OL9-116 was studied after intragastric administration of the compound to healthy and tumor mice at a dose of 150 mg/kg. It was found that maximal concentration of the agent in organs of healthy mice can reach 100 µg/g followed by its distribution and excretion. In tumor mice we observed increasing concentration of OL9-116 during first 1 h after administration to a level of 5-30 µg/g depending on the tissue (lungs, liver, kidneys, tumor node) and remaining at this level for at least next 12 hours, thus showing a pharmacokinetics profile clearly differing from that of healthy animals.