Molecular docking and in silico screening of 2-((4-amino-5-(thiophen-2-ylmethyl)-4h-1,2,4-triazol-3-yl)thio)ethanoic acid as an antioxidant agent

The targeted search for highly effective and safe antioxidants to counteract the damaging effects of oxidative stress remains a priority in modern medicinal chemistry. 1,2,4-Triazole derivatives incorporating a thiophene moiety represent promising bioactive scaffolds whose conformational flexibility and complementarity with biological targets may be effectively evaluated using computer modeling techniques. The aim of this research was to provide a theoretical substantiation of the antioxidant potential of 2-((4-amino-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)ethanoic acid via molecular docking studies with key enzymes and receptors of the redox system, alongside an integrated in silico evaluation of its pharmacokinetic profile. Methods and Results. Molecular docking was performed using the DockingPie plugin within the PyMOL software package against the active sites of six redox-associated targets: peroxiredoxin (PDB ID: 3MNG), nitric oxide synthase (PDB ID: 6NGJ), NAD(P)H oxidase (PDB ID: 2CDU), tyrosinase (PDB ID: 3NM8), NMDA receptor (PDB ID: 4KFQ), and heme oxygenase (PDB ID: 1N3U). The docking protocol was validated via redocking of the native ligands. Physicochemical parameters and the ADMET profile were predicted using the SwissADME platform. Based on the virtual screening results, binding free energy (ΔG) values were determined. The investigated compound displayed high affinity for most of the enzymes. The most prominent result was achieved obtained for tyrosinase (ΔG = -7.199 kcal/mol), where the ligand outperformed the native inhibitor (kojic acid). Complex stabilization is driven by a network of hydrogen bonds with the residues His60, His42, Asn205, and Gly216, as well as specific pi-Sulfur and pi-cation interactions with Phe197 and Arg209. SwissADME screening confirmed full compliance with Lipinski’s Rule of Five, with zero violations. The consensus Log P value is 1.14. The compound exhibits high intestinal absorption, potential blood-brain barrier (BBB) permeability, and an acceptable toxicity profile (Toxicity Class III, LD50 = 2.13 mol/kg) with no predicted mutagenic or carcinogenic risks. The findings of this integrated in silico study highlight the potential of 2-((4-amino-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)ethanoic acid as a potential antioxidant agent and justify its further in vitro and in vivo evaluation as a promising lead scaffold for the development of novel metabolitotropic drugs.