Molecular docking and dynamics simulations of 4-heteroarylidenamino-4,5-dihydro-1H-1,2,4-triazol-5-one derivatives as potential anticancer agents.

The search for anticancer therapies remains imperative, as many existing treatments are hindered by drug resistance, limited efficacy, and undesirable side effects. This study explores the anticancer potential of four 4-heteroarylidenamino-4,5-dihydro-1H-1,2,4-triazol-5-one derivatives using molecular docking and molecular dynamics simulations. These compounds were evaluated against crucial cancer-related proteins, including kinases, histone demethylases, and metabolic regulators. Binding affinity analysis revealed that some derivatives exhibited comparable or superior docking scores to commercial inhibitors such as Imatinib. Compound 1d showed high binding affinities, -7.882 kcal/mol, -9.107 kcal/mol, and -8.474 kcal/mol, for human histone deacetylase 6 catalytic domain 2, A2A adenosine receptor, and human tyrosinase-related protein one mutant (TYRP1), respectively, suggesting strong interactions with key cancer targets. Molecular dynamics simulations confirmed the stability of ligand-protein complexes, with root mean square deviation values below 2.5 Å, indicating minimal conformational fluctuations. Additionally, root mean square fluctuation values ranged from 0.8 to 1.5 Å, supporting stable binding interactions, and the radius of gyration values between 20.2 and 22.5 Å highlighted the compact structural integrity of the complexes. Among the tested ligands, compound 1d demonstrated exceptional binding affinity and stability across multiple targets, particularly the A2A adenosine receptor and TYRP1, which are highly related to epigenetic regulation and cancer progression. These findings suggest that triazole derivatives could serve as promising anticancer agents, warranting further experimental validation to assess their therapeutic potential.