In silico study of the anti-inflammatory potential of new thiopyrimidine derivatives with 1,2,4-triazole as inhibitors of key inflammatory targets

Chronic inflammation is a major pathogenetic factor in the development of numerous serious diseases, including rheumatoid arthritis, atherosclerosis, neurodegenerative disorders, and various cancers. One of the key approaches in the development of new anti-inflammatory agents involves the search for effective and selective cyclooxygenase-2 (COX-2) inhibitors with an improved safety profile. Heterocyclic systems, particularly molecular hybrids of 1,2,4-triazole and thiopyrimidine, are of particular interest due to their potential to exhibit broad biological activity through the synergistic effects of pharmacophoric fragments. This study aims to evaluate, using in silico methods, the potential anti-inflammatory activity of a series of S-derivatives of 4-methyl-5-((pyrimidin-2-ylthio)methyl)-4H-1,2,4-triazole-3-thiols, modified with pyrimidine-2,4(1H,3H)-dione residues. Molecular docking was conducted for 12 novel compounds against the active sites of three key inflammatory targets: COX-2 (PDB ID: 5F1A), inducible nitric oxide synthase (iNOS, PDB ID: 1NSI), and IκB kinase (IKK, PDB ID: 3RZF). The docking was performed using AutoDock Vina, followed by analysis of binding energies and interaction types with the amino acid residues of the target proteins. Aspirin® and Analgin® were used as reference drugs. The results indicate that most of the tested derivatives exhibit high affinity for COX-2, iNOS, and IKK, forming stable complexes with binding energies ranging from -8.2 to -9.6 kcal/mol ‒ values that are comparable to or exceed those of the reference drugs. Favorable hydrogen bonding and hydrophobic interactions with key active-site residues were observed. These in silico findings highlight the promising potential of the studied S-derivatives of 1,2,4-triazole as multifunctional inhibitors of inflammatory mediators. Their high affinity for multiple targets suggests the feasibility of further research aimed at developing new anti-inflammatory agents with a combined mechanism of action.