Messasma_2025_Comput.Biol.Chem_120_108699

Hereby, the in vitro biological, electrochemical, computational, molecular docking, and in silico ADMET properties of the H(2)L ligand have been investigated. The antioxidant potential was evaluated using spectrochemical as well as electrochemical assays. H(2)L was found to exhibit intriguing antioxidant capacities in almost several in vitro applications of tests such as DPPH, ABTS, GOR, PRAC, reducing power, CUPRAC, phenanthroline, and the optical properties of silver nanoparticles (SNPs). The H(2)L showed scavenging ability against electrochemically generated superoxide anion radical (O(2)(.-)) by electrochemical reduction of O(2) quantitated in terms of I %. Furthermore, H(2)L was tested for some enzymatic inhibition activities (cholinesterase, tyrosinase, urease, and alpha-amylase), displaying higher inhibition toward these selected enzymes. A theoretical study was carried out by the density functional (DFT) method (gas phase/B3LYP functional associated with the 6-31G (d,p) basis) for thermodynamic behavior, stability, and reactivity prediction. Then, a docking study was performed using AutoDock and MG-tools programs with the same selected proteins with PDB IDs as follows: 4EY7, 4BDS, 2Y9X, 3LA4, and 2QV4, respectively, to visualize the best docked pose and favorable ligand-protein binding interactions. The in silico results revealed that H(2)L exhibited stronger tyrosinase inhibitory activity than kojic acid. Thus, these results showed good agreement with the experimental data obtained from the enzyme-inhibiting assay. Finally, several important physicochemical descriptors were examined through in silico ADMET analysis and additionally processed through in vitro PAMPA-BBB permeability assay. Finally, to identify the optimal combinations with the antioxidant responses and based on the results obtained from the response surface methodology (RSM), optimization analyses were also carried out.