Actuality. The development of anti-inflammatory drugs occupies an important role in the field of modern pharmacology. Cyclooxygenases (COX-1 and COX-2) are the key enzymes involved in the arachidonic acid cascade. Classical non-steroidal anti-inflammatory drugs (NSAIDs) are diverse group of compounds used for the treatment of inflammation exerting their anti-inflammatory, analgesic, and antipyretic effects through the non-selective inhibition of both COX isoforms. In the past decade fused thiazole-based derivatives became an integral part of new anti-inflammatory agents’ discovery. A wide range of synthetic thiazole-bearing derivatives have been studied for their anti-inflammatory properties including COX-1/COX-2 inhibitory action [1].

The objectives. Introduction of molecular modeling methods within the computer-aided drug discovery process allows to minimize the time and costs for construction and development of new biologically active substances and may accelerate and facilitate the identification of novel COX-1/2 inhibitors among fused thiazole-scaffold bearing compounds.

Materials and methods. The objects of the precent research were three series of 37 N³, C⁵ and C⁶ substituted 3H-thiazolo[4,5-b]pyridine-2-one derivatives, synthesized at Danylo Halytsky Lviv National Medical University.  Probing the action mechanism of thiazolopyridines as anti-exudative agents was performed through molecular docking studies towards COX1/2. Docking, filtering and poses grouping according to the Estimated Affinity were carried out using SeeSar13.1.0 software [2].

Results. The structures of COX-1 in complex with Celecoxib (PDB entry 3KK6) and human COX-2 in complex with Rofecoxib (PDB entry 3KK6) were downloaded from Protein Data Bank. Co-crystalized ligands were extracted from the binding sites. Docking of the set of 37 ligands, Mefenamic acid and Ibuprofen as references were carried out utilizing two workflows: Standard docking and Template Docking. Visual inspection of poses and their Lipophilic Ligand efficiency (LLE) evaluation led us to choose Template docking outcomes with Ibuprofen as the template for further analysis. All poses were checked and transferred to the Analyzer Mode. Molecules were grouped by the pose of each compound with the best estimated activity. The analysis of docking results against COX-1 allowed to conclude, that all docked ligands had the proper orientation in the binding site of COX-1, most common amino acid residues of the protein for hydrogen binding with ligands were ARG-120 and SER-530, the HYDE scores of the most active ligands exceed that ones for Celecoxib.

  Docking results against COX-2 revealed that hydrogen bonds in most ligand-receptor complexes were formed between Oxygen atom of thiazole ring and TYR-355 amino acid residue. Favourable HYDE scores corresponded to Sulfur atom of thiazole ring and/or C³ and C⁵ carbons of phenyl substituent in N³ position of fused scaffold contributions. Non-favorable contributions referred to Oxygen atom of thiazole ring. At the same time, in both docking procedures for the ligands under study their Estimated Affinity towards COX-2 was significantly lower than that one for Ibuprofen despite they were able to achieve proper orientations.

Conclusions. The number of hit compounds under study showed high Estimated Affinity, proper binding orientation and significant HYDE scores towards proposed protein targets. However, no exact correlation between experimental pharmacological activities and docking scores was found.

Acknowledgement: O. K. thanks Universidad San Pablo CEU for a Postdoctoral Contract for Ukrainian Researchers 2022-2024.

Introduction. Nitrogen-based heterocycles are an extremely important class of organic substances widely used in medicinal chemistry, since more than 60% of drugs and more than 85% of biologically active substances described in the literature contain a Nitrogen-containing heterocycle in their structure. The оbjective of thе prеsent study wаs to synthеsize sоme nоvel antiоxidant аgеnts viа a structurаl mоdification оf еarly оbtainеd 3-(5-mercapto-[1,3,4]oxodiazole-2-yl-methyl)-5,7-dimethyl-3H-thiazolo[4,5-b]pyridine-2-one fоr furthеr pharmаcological scrеening in vitrо as antiоxidants.

Results and discussion. For broadening the scope of mercapto substituteds thiazolo[4,5-b]pyridines, we involved 3-(5-mercapto-[1,3,4]oxodiazole-2-yl-methyl)-5,7-dimethyl-3H-thiazolo[4,5-b]pyridine-2-one into cynoethylation reaction taking the advantage of the good leaving hydrogen atom property of the SH-group. It is established that the most optimal conditions for the introduction of the β-cyanoethyl fragment on the base scaffold thiol group consists of the interaction of 3-(5-mercapto-[1,3,4]oxodiazol-2-yl-methyl)-5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-2-one with acrylonitrile in a pyridine-water medium at a ratio of 5:1, this made it possible to obtain the corresponding 3-[5-(5,7-dimethyl-2-oxothiazolo[4,5-b]pyridin-3-ylmethyl)-[1,3,4]oxodiazol-2-ylsulfanyl-propionitrile. Obtained through the mentioned above reaction compound was subjected to hydrolysis leading to 3-(5-hydroxy-7-methyl-2-oxothiazolo[4,5-b]pyridin-3(2H)-yl) propanoic acid formation. For carboxyl group transformation, the corresponding chloranhydride, which belongs to unstable highly reactive reagents was obtained, so its application in further transformations was carried out without isolation by introducing aromatic amines acylation. The above conversion allowed to obtain a number of suitable propionamides. The antioxidant activity of the synthesized compounds was measured in vitro by the method of scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals. The present results of аntioxidant  activity have shown that the synthesized compounds demonstrated considerable аntioxidant  effects. Further optimization of the structure to improve biological activity is currently in progress. Conclusions. A sеries of thiazоlo[4,5-b]pyridinе-2-ones pоssessing аntioxidant аctivities wеre preparеd by the structurаl mоdification of thе cоre heterоcycle. Whеn cоmpared with еxisting аntioxidants, some оur cоmpounds wеre fоund to bе mоre potеnt. Thus the cоre fused heterocyclе mаy be cоnsidered as a prоmising scаffold for аntioxidant drug cаndidates devеlopment.

Multitarget directed ligands as a modern approach for drug design has gained increasing attention in the recent decades as a more effective therapeutic strategy, especially in the framework of multifactorial diseases including cancer, leading to synergistic anti-tumor effects and reduced drug-drug interactions.

The systematic development of CK2/HDAC dual inhibitors held by Drug Design and Synthesis Research Group at San Pablo CEU University led to novel dual-target ligands construction through the pharmacophores combining of Tucidinostat as zinc-binding group (ZBG) chelating Zn²⁺ cation at the catalytic domain of HDAC1, and CX-4945 as the competitive CK2 inhibitor, which also acts as Surface Recognition Domain (Cap group) in HDACs. Alkyl linear chains of varying length and alkyl chains incorporating phenyl or/and triazole motifs were introduced as the Linkers to connect the Cap structure to the ZBG.  

The objective was to discover the impact of the linkers` composition on the conformational behavior of the dual inhibitors in explicit water and chloroform environments. The workflow included geometry optimization with Gaussian16 followed by 100 ns MD simulations using Amber 16 suite [4]. Trajectory analysis with cpptraj allowed to retrieve the molecular descriptors which are essential to predict cell permeability and characterize conformers’ shape (radius of gyration), polarity (Polar surface area) and the ability to fold (the number of intramolecular hydrogen bonds and ZBG-Cap mass-centered distance). Clustering analysis of generated conformers resulted in 10 clusters which represent the most probable and stable conformations.

Objectives: this study aimed to assess the effectiveness of artificial intelligence on education, focusing on how it can be leveraged to personalised learning experiences tailored to the specific needs of students. Study Design: a comprehensive literature review was conducted, alongside an analysis of psychological factors that influence student motivation. Place and Duration of the Study: relevant academic sources and case studies were reviewed over the duration of six months to gather insights on AI applications in education. Sample: the sample consisted of the scientific thought and scientists that have integrated AI technologies into their curricula. Method: a qualitative analysis from literature was utilised in this research to evaluate AI tools’ effectiveness in enhancing personalised learning outcomes. Results: the findings indicate that ChatGPT is currently the most widely utilised AI tool in educational contexts, demonstrating a significant capacity to personalised learning by adapting it to individual psychological profiles and learning paces. Conclusion: the integration of AI technologies in education presents unprecedented opportunities for curriculum personalisation and student engagement. However, it also necessitates careful consideration of ethical issues, especially related to learner data privacy, to ensure responsible implementation.

ABSTRACT
The aim: The objective of the research was to study the indicators of oxidative modification of proteins (OMP) and the activity of matrix metalloproteinase-9 (MMP-9) in patients with paranoid schizophrenia depending on the disease duration.
Materials and methods: 320 patients were included in the examination. 20 patients were with “Primary psychotic episode” (Comparison Group) and 300 patients were diagnosed with “Paranoid schizophrenia” (Experimental Group): 60 of them have suffered from this disease for a duration from 3 to 5 years (Subgroup I ); 60 patients have sufferedfor a period from 6 to 10 years (Subgroup II); 60 individuals – from 11 to 15 years (Subgroup III); 60 patients have suffered for a duration from 16 to 20 years (Subgroup IV); 60 patients – from 21 years and longer (Subgroup V).
Results: The presented data showed that the levels of OMP indicators in Subgroup I constituted 0.826±0.046 conventional units at a wavelength of 356 nm; 0.864±0.051 conventional units at a wavelength of 370 nm; 0.444±0.019 conventional units at a wavelength of 430 nm; 0.176±0.007 conventional units at a wavelength of 530 nm, which is 1.99; 1.6; 1.13 and 1.43 times higher than in the Comparison Group. The content of OMP products was higher by 2.24; 1.74; 1.17, and 1.43 times in Subgroup II, respectively, by 2.4; 1.80; 1.36 and 1.46 times in Subgroup III, respectively;by 2.5; 1.9; 1.4; 1.6 times in Subgroup IV, respectively; by 2.5; 2.02; 1.54; 1.7 times in Subgroup V, respectively. The conducted correlation analysis indicated a direct correlation between OMP indicators and the disease duration. The concentration of MMP-9 in the patients of the Comparison Group was equal to 892.84±87.80 pg/ml, which was 11.2% less compared to the Experimental Subgroup I, where this indicator was 992.84±67.50 pg/ml. MMP-9 constituted 1092.53±47.20 pg/ml on average in the patients of Subgroup II, which was 22.36% higher than in the Comparison Group. This indicator was 1702.84±37.60 pg/ml in Subgroup III, which was 90.7% higher than in the Comparison Group. It constituted 1492.84±47.29 pg/ml in Subgroup IV, which was 67.2% higher than in the Comparison Group;and 2037.21±57.80 pg/ml in Subgroup V, which was more than two times higher than in the Comparison Group (p<0.05). The conducted correlation analysis showed a direct relation between MMP-9 expression and the increase in OMP indicators. This relation was more significant between MMP-9 and OMP products of a neutral nature. The correlation strength between MMP-9 and OMP products of a basic nature was somewhat less significant.
Conclusions: According to the results of the conducted analysis, the examined patients hadthe signs of decompensation of reactive-adaptive biomolecular mechanisms which activated radical reactions with the subsequent accumulation of oxidation products.