AN IN SILICO EVALUATION OF NOVEL 1,2,4-TRIAZOLE SCHIFF BASE DERIVATIVES AS POTENTIAL GABA-A RECEPTOR MODULATORS USING MOLECULAR DOCKING AND ADMET ANALYSIS

Abstract

The present study focuses on the computational assessment of novel 1,2,4 – Triazole Schiff base compounds as possible ligands targeting the GABA-A receptor for anticonvulsant activity. A series of 20 structurally diverse 1,2,4 – Triazole Schiff bases (Z)-4-[(substitutedmethylene)amino]-5-phenyl-4H-1,2,4-triazole-3-thiols (AKS – 1 – AKS – 20) were designed and subjected to molecular docking using Auto Dock Tools 1.5.7 against the GABA-A receptor (PDB ID: 6X3Z), indicating strong binding affinities for compounds 4-(2-chloro-4 methylbenzylideneamino)-5-phenyl-4H-1,2,4-triazole-3-thiol (AKS – 1), 4-(3-chloro-4 methoxybenzylideneamino)-5-phenyl-4H-1,2,4-triazole-3-thiol (AKS – 3) and 4-(2-chloro-3-hydroxy-4 methoxybenzylideneamino)-5-phenyl-4H-1,2,4-triazole-3-thiol (AKS – 7), with docking scores of -9.4, -10.1 and -9.1 kcal/mol, respectively. These three active compounds were also subjected to ADMET analysis to evaluate their pharmacokinetic behaviour, and drug-likeness properties. Molecular docking studies against the GABA-A receptor revealed significant interactions of the synthesized derivatives contains important residues of amino acids within the site that is active, indicating favourable receptor affinity and possible agonistic activity. ADMET prediction and Lipinski’s rule analysis demonstrated that compounds AKS - 1, AKS - 3, and AKS – 7 possess acceptable pharmacokinetic profiles, good oral bioavailability, and low toxicity. Among the evaluated derivatives, compounds AKS - 1, AKS - 3, and AKS – 7 exhibited stable intermolecular connections and nearly same X, Y, Z coordinates to the reference ligand (phenytoin) of GABA-A receptor (PDB ID: 6X3Z), suggesting their potential as promising anticonvulsant agents.